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Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b5463 (Published 13 January 2010) Cite this as: BMJ 2010;340:b5463

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  1. The DIPART (vitamin D Individual Patient Analysis of Randomized Trials) Group
  1. Correspondence to: B Abrahamsen, Department of Internal Medicine and Endocrinology, Copenhagen University Hospital Gentofte, Niels Andersensvej 65, DK-2900 Hellerup, Denmark b.abrahamsen{at}physician.dk
  • Accepted 23 October 2009

Abstract

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium.

Design Individual patient data analysis using pooled data from randomised trials.

Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men).

Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants.

Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use.

Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy.

Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.

Footnotes

  • We are grateful to the authors of the original trial reports: G B Smedshaug, E Kvaavik, J A Falch, A Tverdal, J I Pedersen, H Raphael, P Maslin, S Crozier, E R Larsen, A Foldspang, A M Grant, M K Campbell, A M McDonald, G S MacLennan, G C McPherson, C Donaldson, W J Gillespie, C M J Robinson, W A Wallace, M Gass, R B Wallace, C E Lewis, T Bassford, S A Beresford, H R Black, P Blanchette, D E Bonds, R L Brunner, R G Brzyski, B Caan, J A Cauley, R T Chlebowski, S R Cummings, I Granek, J Hays, G Heiss, S L Hendrix, B V Howard, J Hsia, F A Hubbell, K C Johnson, H Judd, J M Kotchen, L H Kuller, R D Langer, N L Lasser, M C Limacher, S Ludlam, J E Manson, K L Margolis, J McGowan, J K Ockene, M J O’Sullivan, L Phillips, R L Prentice, G E Sarto, M L Stefanick, L Van Horn, E Whitlock, G L Anderson, A R Assaf, D Barad, R A Lyons, S Brophy, R G Newcombe, C J Phillips, B Lervy, R Evans, M D Stone, K Wareham, J Porthouse, S Cockayne, C King, L Saxon, E Steele, T Aspray, M Baverstock, Y Birks, J Dumville, C Iglesias, S Puffer, A Sutcliffe, and I Watt. We thank the WHI investigators and staff for their dedication and the study participants for making the programme possible. A full listing of WHI investigators can be found at www.whiscience.org/publications/WHI_investigators_shortlist.pdf.

  • DIPART Group: B Abrahamsen, professor, Department of Medicine F, Copenhagen University Hospital Gentofte, Hellerup, and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; T Masud, professor, Geriatric Medicine, Nottingham University Hospitals, Nottingham; A Avenell, clinical senior lecturer, Health Services Research Unit, University of Aberdeen, Aberdeen; F Anderson, clinical senior lecturer, Geriatric Medicine, DOHaD Research Division, University of Southampton School of Medicine, Southampton; H E Meyer, professor, Division of Epidemiology, Norwegian Institute of Public Health, and Section for Preventive Medicine and Epidemiology, Oslo University of Oslo, Oslo, Norway; C Cooper, professor, MRC Epidemiology Resource Centre, Southampton; H Smith, professor, Public Health and Primary Care, Brighton and Sussex Medical School, Brighton; A Z LaCroix, professor, Public Health, Fred Hutchinson CRC, Seattle, WA, USA; D Torgerson, professor, York Trials Unit, University of York, York; A Johansen, consultant, Department of Public Health, Swansea University, Swansea, and Academic Department of Geriatric Medicine, University Hospital of Wales, Cardiff; R Jackson, professor, Endocrinology, Ohio State University, Columbus, OH, USA; L Rejnmark, staff specialist, Endocrinology, Aarhus University Hospital, Aarhus, Denmark; J Wactawski-Wende, professor, Departments of Social and Preventive Medicine and Gynecology-Obstetrics, University at Buffalo, Buffalo, NY, USA; K Brixen, clinical associate professor, Institute of Clinical Research, University of Southern Denmark, Odense, and Endocrinology, Odense University Hospital, Odense, Denmark; L Mosekilde, professor, Endocrinology, Aarhus University Hospital; J A Robbins, professor, Internal Medicine, University of California at Sacramento, CA, USA; R M Francis, professor, Geriatric Medicine, Freeman Hospital, Newcastle.

  • Contributors: BA, TM, KB, JAR, LM, and RMF conceived and designed this joint analysis. BA and LR acquired and analysed the data. BA, TM, AA, HS, LR, JWW, KB, JAR, LM, and RMF drafted the article. All members of the DIPART Group contributed to revising the manuscript critically and approved the final version, as well as contributing to the interpretation of the joint results and to the design of their individual trials. BA is the guarantor.

  • Funding: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. AA acknowledges personal funding from the UK Medical Research Council and Chief Scientist Office of the Scottish Government Health Directorates.

  • Competing interests: BA receives consulting fees from Novartis, serves on advisory boards for Amgen and Nycomed, and receives lecture fees from Eli Lilly and Procter & Gamble. TM receives research funding and speakers’ fees from Merck, Procter & Gamble, Roche, Eli Lilly, Shire, ProStrakan, and Servier. FA has received honorariums for lectures and advisory panels from Shire, Celltech, ProStrakan, and Merck. CC has served in a consultant capacity to the Alliance for Better Bone Health, Eli Lilly, Merck Sharp & Dohme, Amgen, GlaxoSmithKline, Roche, and Servier. DT has received research funding from Shire Pharmaceuticals. ALC serves on advisory boards for studies funded by Pfizer, Procter & Gamble, and Sanofi-Aventis. KB has received consultancy fees from Servier, Novartis, Eli Lilly, Nycomed, and Osteologix, as well as speakers’ fees from Eli Lilly, Novartis, and Servier and research grants from Merck Sharp & Dohme. RMF has served as an adviser to Procter & Gamble, Sanofi, Merck Sharp & Dohme, Roche, GlaxoSmithKline, Novartis, Lilly, Servier, Nycomed, Shire, and Prostrakan.

  • Ethical approval: Not needed.

  • Data sharing: Varies by trial; please contact study leads of primary trials.

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