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RESEARCH: H A Bischoff-Ferrari, B Dawson-Hughes, H B Staehelin, J E Orav, A E Stuck, R Theiler, J B Wong, A Egli, D P Kiel, and J Henschkowski Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials BMJ 2009; 339: b3692 [Abstract] [Full text]

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Time for a moratorium on meta-analyses of vitamin D?

Mark J Bolland, Andrew Grey, Ian R Reid   (6 October 2009)

Lack of correlation between supplemental vitamin D prescription and serum vitamin D concentrations

Maria Juarez, Priyani Wanigasekara , Lyn Williamson   (16 October 2009)

Information on harm is missing

Gabriele Meyer, Sascha Köpke   (20 October 2009)

Time for a moratorium on meta-analyses of vitamin D? 6 October 2009
Mark J Bolland, Senior Research Fellow Department of Medicine, University of Auckland, Auckland 1142, New Zealand, Andrew Grey, Ian R Reid Send response to journal: Re: Time for a moratorium on meta-analyses of vitamin D?	In 2003, Latham et al. performed a systematic review and meta- analysis of the effect of vitamin D or its metabolites on falls, and concluded there was no effect [1]. Subsequently, there have been at least eight further meta-analyses of trials of vitamin D and its metabolites/analogues and falls, including that recently reported by Bischoff-Ferrari et al. [2]. Of the nine reviews, four reported a positive effect of vitamin D or its metabolites/analogues on falls, and five no effect, or benefits limited to certain subgroups. The differences between the conclusions of the reviews often depend on selection of studies for inclusion in the primary and secondary analyses, and the grounds for exclusion sometimes seem capricious. For example, a negative study [3] was excluded from the most recent meta-analysis [2] because patients were “in an unstable health state”, even though this was not specified in the inclusion criteria and this label could apply to many of the people who will be treated based on the conclusions of this meta-analysis. There are relatively few randomised controlled trials (RCT) on the topic of vitamin D and falls. In the most recent review [2], 10 studies of 3050 participants were included in the primary analysis and 17 studies in the sensitivity analyses [2]. The ratio of the number of RCTs to meta- analyses (RCT:Met) [4] for vitamin D and falls is 17:9 or 1.9. Similarly, there are at least 14 published meta-analyses on vitamin D and fracture prevention, but only 22 RCTs were included in the most recent Cochrane review [5]. Again, conclusions differ substantially between reviews. Most reviews reported no effect of vitamin D overall, but positive effects on fracture incidence were reported in some subgroups, including those receiving high dose vitamin D, or calcium and vitamin D co -supplementation, and individuals in residential care. The RCT:Met for vitamin D and fractures is 22/14 or 1.6. We continue to be concerned that, in some areas of medicine, too much emphasis is being placed on analysis and re-analysis of a limited amount of trial-level data by meta-analysis, rather than on the design and conduct of informative RCTs in relevant populations [4]. The conflicting conclusions generated by this practice have the potential to cause considerable confusion among health practitioners. We suggest that no further meta-analyses are conducted on the topics of vitamin D and falls or fractures until additional adequately powered RCTs are performed, thereby permitting a meaningful re-evaluation. References: 1. Latham NK, Anderson 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;51:1219-26. 2. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692. 3. Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID. A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS). J Am Geriatr Soc 2003;51:291-9. 4. Bolland MJ, Grey A, Reid IR. The randomised controlled trial to meta-analysis ratio: original data versus systematic reviews in the medical literature. N Z Med J 2007;120:U2804. 5. Avenell A, Gillespie WJ, Gillespie LD, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009:CD000227. Competing interests: None declared
Lack of correlation between supplemental vitamin D prescription and serum vitamin D concentrations 16 October 2009
Maria Juarez, Rheumatology Registrar The Great Western Hospital NHS Foundation Trust. Swindon. SN3 6BB, Priyani Wanigasekara , Lyn Williamson Send response to journal: Re: Lack of correlation between supplemental vitamin D prescription and serum vitamin D concentrations	Bischoff-Ferrari and colleagues report that vitamin D supplementation (700-1000 IU daily) may reduce falls by 19% to 26% amongst individuals aged 65 years or older. They emphasise that no fall reduction was observed for serum vitamin D concentrations below 60 nmol/l. We agree it is important to identify low vitamin D levels in this population group as this may result in falls and fractures. High prevalence of hypovitaminosis D in this age group is recognised (1) and is particularly important in those patients at high risk of falling such as rheumatology patients (2). This is particularly important in patients who are receiving treatment with bisphosphonates, as these drugs may cause clinically significant hypocalcaemia in the presence of low vitamin D (3). The new long-acting powerful intravenous bisphosphonates, such as zoledronic acid, are increasingly used because of improved compliance and tolerability. The risk of hypocalcaemia is greater with the more potent preparations and we have previously reported the case of a patient with unrecognized hypovitaminosis D who developed rapid life threatening-hypocalcaemia after zoledronic acid administration (4). This experience led us to review our practice regarding patients receiving intravenous Zoledronic acid. Over the last year 43 patients received intravenous Zolendronic acid: 65% female, mean age 73.7 years, diagnosis: 58% osteoporosis, 40% Paget’s disease, 2% osteogenesis imperfecta. Only 32.5% of patients had serum vitamin D levels measured before treatment. Of those tested, 35.7% had low vitamin D levels (<20 ng/ml). Interestingly, all patients with low vitamin D levels had already been prescribed oral vitamin D supplementation. Of the patients with adequate levels, serum vitamin D (64.3%), 44.4% were on oral vitamin D supplements and 55.6% were not. Our data suggests that there is no correlation between prescription of vitamin D supplementation and serum levels of vitamin D. The explanation for this is likely to be multifactorial, including lack of patient compliance, and prescription of inadequate preparation or dose of vitamin D supplements. It is important that clinicians recognise this and ensure that patients have fully replenished vitamin D stores prior to intravenous bisphosphonate therapy. It is also important to remember to consider the dose, preparation, absorption and compliance with vitamin D replacement (5). 1. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81:353-73. 2. Mouyis M, Ostor AJK, Crisp AJ, Ginawi A, Halsall DJ, Shenker N et al. Hypovitaminosis D among rheumatology outpatients in clinical practice. Rheumatology 2008;47:1348-51. 3. Whitson HE, Lobaugh B, Lyles KW. Severe hypocalcaemia following bisphosphonate treatment in a patient with Paget’s disease of the bone. Bone 2006;39:954-8. 4. Joshi A, Price E, Collins D, Williamson L. Comment on: Hypovitaminosis D among rheumatology patients in clinical practice. Rheumatology 2009;48:203-4. 5. Ryan PJ. Vitamin D therapy in clinical practice. One dose does not fit all. Int J Clin Pract 2007;61:1894-9. Competing interests: None declared
Information on harm is missing 20 October 2009
Gabriele Meyer, Professor of Clinical Nursing Research University of Witten/Herdecke, 58453 Witten, Germany, Sascha Köpke Send response to journal: Re: Information on harm is missing	The effects of vitamin D supplementation on muscle strength, function and balance and its efficacy on accidental fall prevention have been subject of a number of systematic reviews over the last years. We have read the meta-analysis by Bischoff-Ferrari et al. (1) with astonishment since there is no consideration of potential side effects of vitamin D and its toxicity. Thus, the meta-analysis is another piece of evidence indicating that harms of treatment options are regularly underreported, even when the information is accessible in primary studies (2). Omission of a treatment’s side effects, however, leads to an overoptimistic estimate of the expected benefits and does not provide the necessary information for informed decision making. Balancing the pros and cons of a treatment is especially important in preventive options since patients and consumers are confronted with decisions on long-term treatment targeting events that might (or might not) occur in the remote future. Coverage of adverse events has long been a key feature of good clinical reporting which has also been recognised by the recent PRISMA statement (3). Vitamin D and its analogues are not harmless. Gastrointestinal symptoms and renal disease have been reported (4). Bischoff-Ferrari and colleagues are therefore requested to prepare an amendment on the side effects and toxicity of vitamin D. Since randomised controlled trials often do not adequately reflect the underlying risk-benefit profiles of treatment options (5) inclusion of observational evidence might be necessary in order to enhance judgement of the applicability of the findings. As long as proper information on harm is missing, the meta-analysis by Bischoff-Ferrari (1) does not allow for an unbiased and objective judgement of the balance between risks and benefit of vitamin D. Meta-analyses defining the objective of their review as only assessing efficacy of an intervention rather than assessing efficacy and safety should be regarded as outdated. References (1) Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009 Oct 1; 339: b3692. doi: 10.1136/bmj.b3692 (2) Papanikolaou PN, Ioannidis JP. Availability of large-scale evidence on specific harms from systematic reviews of randomized trials. Am J Med 2004; 117: 582-9 (3) Liberati A, Altman DA, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. Ann Intern Med 2009; 151: W-65-94 (4) Avenell A, Gillespie WJ, Gillespie LD, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009; (2): CD000227 (5) Gartlehner G. Assessment of adverse effects and applicability- two areas not (yet) covered adequately in Cochrane reports. Z Evid Fortbild Qual Gesundhwes 2008; 102: 497-502 Competing interests: None declared