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NIHR Health Technology Assessment programme: Executive Summaries.

Vitamin K to prevent fractures in older women: systematic review and economic evaluation

M Stevenson, M Lloyd-Jones, and D Papaioannou.

Author Information

M Stevenson,* M Lloyd-Jones, and D Papaioannou.

University of Sheffield, School of Health and Related Research (ScHARR), UK
* Corresponding author

Published: 2009.

Description of proposed service

The focus of this report is to establish whether vitamin K can be used cost-effectively in the treatment of women who are osteoporotic and who have a previous fracture.

Epidemiology and background

Osteoporosis is a common disease in the elderly, with an estimated 0.95 million female sufferers in England and Wales. It is defined as possessing a T-score (the number of standard deviations from the average bone mineral density of healthy young women) of –2.5 standard deviations or lower. The main consequence of osteoporosis is an increased incidence of fractures, which increase as a woman ages. These result not only in morbidity for the patient (with a risk of mortality following fractures at some sites) but also in the consumption of scarce NHS resources. A recent estimate of the projected cost of osteoporotic fractures in women in the UK by 2010 put this figure at £2.1 billion.


The scope of this assessment was to determine the clinical effectiveness and cost-effectiveness of vitamin K in preventing osteoporotic fractures in postmenopausal women compared with either no vitamin K or specific drugs licensed in the UK for the prevention or treatment of postmenopausal osteoporosis. Relevant outcome measures included incident vertebral and non-vertebral fractures; health-related quality of life; all-cause mortality; and adverse effects of treatment.

Searches to identify relevant studies were conducted in 14 electronic databases [MEDLINE, MEDLINE In-Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, AMED, NRR (National Research Register), Science Citation Index and Current Controlled Trials]. The searches were undertaken in May 2007 and the MEDLINE search was updated in March 2009. The searches were not restricted by publication type, date of publication or language.

The inclusion criteria were as follows:

  • Population: postmenopausal women with osteoporosis/osteopenia.
  • Intervention: oral vitamin K (any dose).
  • Comparators:
  • Outcomes: all-cause mortality; incident vertebral fracture; incident non-vertebral fracture; adverse effects; continuance; compliance, health-related quality of life; costs incurred.
  • Study design: randomised controlled trials; economic evaluations.

Only randomised controlled trials (RCTs) that reported fracture outcomes were included in the review of clinical effectiveness; however, this criterion was relaxed for consideration of adverse events, allowing inclusion of observational studies or RCTs that did not report fracture outcomes.

The following studies were excluded: those that were considered methodologically unsound in terms of either study design or method used to assess fractures, or those that did not report results in the necessary detail; or those in which the participants were not vitamin D replete and/or had insufficient calcium intake.

Where appropriate, meta-analysis was carried out, using Review Manager software (REVMAN).

Number and quality of studies and direction of evidence

Five randomised controlled trials were identified that compared vitamin K with a relevant comparator in postmenopausal women with osteoporosis or osteopenia. The double-blind ECKO trial compared 5 mg of phylloquinone (vitamin K1) with placebo in Canadian women with osteopenia but without osteoporosis. Four open-label trials used 45 mg of menatetrenone (vitamin K2) in Japanese women with osteoporosis; the Osteoporosis Fracture (OF) study and that by Shiraki et al. compared menatetrenone with no treatment, the Yamaguchi Osteoporosis Prevention Study (YOPS) compared it with etidronate or no treatment, and the trial by Iwamoto compared it with etidronate or calcium.

The methodological quality of the ECKO trial was good. By contrast, all four trials of menatetrenone were poorly reported, making it impossible to exclude the possibility that their methodological quality was low; moreover, three were very small (< 100 women in each group).

Phylloquinone was associated with a statistically significant reduction in the risk of clinical fractures relative to placebo [relative risk (RR) 0.46, 95% confidence interval (CI) 0.22 to 0.99]; morphometric vertebral fractures were not reported. Although the smaller trials found that menatetrenone was associated with a reduction in the risk of morphometric vertebral fractures relative to no treatment or calcium, the much larger OF study found no evidence of a reduction in vertebral fracture risk. The three smaller trials found no significant difference between treatment groups in non-vertebral fracture incidence. OF study data relating to non-vertebral and clinical vertebral fractures have not been published.


In the ECKO trial, phylloquinone was not associated with an increase in adverse events; moreover, it was possible that it demonstrated anticancer efficacy. In the menatetrenone trials, the reporting of adverse events was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions.

Summary of benefits

Benefits have been measured in terms of quality-adjusted life-years (QALYs). Vitamin K provided gains in QALYs compared with no treatment in women with sufficient calcium and vitamin D intakes. The size of the QALY gain for each intervention was strongly related to the absolute risk of fracture.

Cost-effectiveness of identification and treatment strategies

No published economic evaluations of vitamin K were found. A mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1; the efficacy data for other types of vitamin K were considered too poor to be included. Comparators were two bisphosphonates (alendronate and risedronate) and strontium ranelate. Vitamin K1 and alendronate were seen to be markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures.

Evaluation of further research

Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years’ duration comparing alendronate with vitamin K1. This showed that the costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm, which would be used to influence future prescribing policy, were estimated to be a cost-effective use of resources.


It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered, thus there would be no change in NHS expenditure. Even if vitamin K1 was used, the acquisition prices of alendronate and vitamin K1 are similar and thus there is unlikely to be a marked impact on NHS expenditure.

Conclusions/need for further research

There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. A calculation of the expected value of sampled information has shown that an RCT of 2000 women per arm would be a cost-effective use of resources.


  • Stevenson M, Lloyd-Jones M, Papaioannou D. Vitamin K to prevent fractures in older women: systematic review and economic evaluation. Health Technol Assess 2009;13(45). [PubMed: 19818211]

NIHR Health Technology Assessment programme

The Health Technology Assessment (HTA) programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

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The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 07/16/01. The protocol was agreed in October 2007. The assessment report began editorial review in February 2009 and was accepted for publication in April 2009. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

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PMID: 19818211