David Torgerson

Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial

BACKGROUND Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures. METHODS In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures. FINDINGS 698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups. INTERPRETATION The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.

Guidelines for diagnosis and management of osteoporosis

PreambleSignificant developments have occurred in the field of osteoporosis over the past several years. There is now considerable information concerning its impact on general health and an international consensus concerning the definition of osteoporosis. Conceptually, this recognizes the multifactorial nature of the events which give rise to the fractures, but operational definitions have now been agreed and have gained a wide measure of acceptance. Accurate and precise diagnostic tools are also available. Finally, there is substantial evidence that the natural history of osteoporosis can be modulated by agents which in turn decrease the risk of fracture. Despite an increasing professional and public awareness of osteoporosis, the management of osteoporosis has been confined mainly to specialists. With the large number of affected individuals and the wider availability of diagnostic aids and safe treatments, there is a need for osteoporosis to be managed predominantly by the primary care physician. Against this background the European Foundation for Osteoporosis and Bone Disease through their Scientific Advisory Board has recognized a need to develop practice guidelines for primary care physicians which are summarized in this paper.

Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care

Abstract 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.

General anaesthesia versus local anaesthesia for carotid surgery (GALA): a multicentre, randomised controlled trial

BACKGROUND The effect of carotid endarterectomy in lowering the risk of stroke ipsilateral to severe atherosclerotic carotid-artery stenosis is offset by complications during or soon after surgery. We compared surgery under general anaesthesia with that under local anaesthesia because prediction and avoidance of perioperative strokes might be easier under local anaesthesia than under general anaesthesia. METHODS We undertook a parallel group, multicentre, randomised controlled trial of 3526 patients with symptomatic or asymptomatic carotid stenosis from 95 centres in 24 countries. Participants were randomly assigned to surgery under general (n=1753) or local (n=1773) anaesthesia between June, 1999 and October, 2007. The primary outcome was the proportion of patients with stroke (including retinal infarction), myocardial infarction, or death between randomisation and 30 days after surgery. Analysis was by intention to treat. The trial is registered with Current Control Trials number ISRCTN00525237. FINDINGS A primary outcome occurred in 84 (4.8%) patients assigned to surgery under general anaesthesia and 80 (4.5%) of those assigned to surgery under local anaesthesia; three events per 1000 treated were prevented with local anaesthesia (95% CI -11 to 17; risk ratio [RR] 0.94 [95% CI 0.70 to 1.27]). The two groups did not significantly differ for quality of life, length of hospital stay, or the primary outcome in the prespecified subgroups of age, contralateral carotid occlusion, and baseline surgical risk. INTERPRETATION We have not shown a definite difference in outcomes between general and local anaesthesia for carotid surgery. The anaesthetist and surgeon, in consultation with the patient, should decide which anaesthetic technique to use on an individual basis. FUNDING The Health Foundation (UK) and European Society of Vascular Surgery.

A UK consensus group on management of glucocorticoid-induced osteoporosis : an update

Abstract. Eastell R, Reid DM, Compston J, Cooper C, Fogelman I, Francis RM, Hosking DJ, Purdie DW, Ralston SH, Reeve J, Russell RGG, Stevenson JC, Torgerson DJ (University of Sheffield Medical School, Sheffield; University of Aberdeen, Aberdeen; University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge; Southampton General Hospital, Southampton; Guys Hospital, London; Freeman Hospital, Newcastle upon Tyne; Nottingham City Hospital, Nottingham; Hull Royal Infirmary, Hull; Wynn Institute for Metabolic Research, London; and the University of York, York, UK). A UK Consensus Group on management of glucocorticoid‐induced osteoporosis: an update (Review). J Intern Med 1998; 244: 271–292.

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

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.

The cost of treating osteoporotic fractures in the United Kingdom female population.

Abstract: Osteoporotic fractures represent a significant burden to society. The costs of osteoporotic fractures to the UK health care system have not previously been accurately described. In this paper, we quantify the health care and social care costs of fractures occurring in women aged 50 years and over in the UK. We used a variety of data sources. For acute hospital hip fracture costs existing published estimates were used whilst for social care costs a survey of resource use among fracture patients before and after hip fracture was utilized. We undertook a case–control study using the General Practice Research Database to estimate primary care costs. From these data we estimated that the cost of a hip fracture is about £12000, with non-acute hospital costs representing the larger proportion. The other fractures were less expensive, at £468, £479 and £1338 for wrist, vertebral and other fractures, respectively. For all fractures the annual cost to the UK is £727 million. Assuming each male hip fracture costs the same as a female fracture, including these would increase the total costs to £942 million.

Evidence for risk of bias in cluster randomised trials: review of recent trials published in three general medical journals

Abstract Objective To examine the prevalence of a risk of bias associated with the design and conduct of cluster randomised controlled trials among a sample of recently published studies. Design Retrospective review of cluster randomised trials published in the BMJ, Lancet, and New England Journal of Medicine from January 1997 to October 2002. Main outcome measures Prevalence of secure randomisation of clusters, identification of participants before randomisation (to avoid foreknowledge of allocation), differential recruitment between treatment arms, differential application of inclusion and exclusion criteria, and differential attrition. Results Of the 36 trials identified, 24 were published in the BMJ,11 in the Lancet, and a single trial in the New England Journal of Medicine. At the cluster level, 15 (42%) trials provided evidence for secure allocation and 25 (69%) used stratified allocation. Few trials showed evidence of imbalance at the cluster level. However, some evidence of susceptibility to risk of bias at the individual level existed in 14 (39%) studies. Conclusions Some recently published cluster randomised trials may not have taken adequate precautions to guard against threats to the internal validity of their design.

Contamination in trials: is cluster randomisation the answer?

Most randomised trials allocate individual participants to different treatments. However, cluster randomised trials in which groups of subjects are allocated to different treatments are becoming increasingly popular.1 Cluster randomisation is often advocated to minimise treatment “contamination” between intervention and control participants. For example, in a trial of dietary change, people in the control group might learn about the experimental diet and adopt it themselves. Contamination of control participants has two related effects. It reduces the point estimate of an interventions effectiveness and this apparent reduction may lead to a type II error—that is, rejection of an effective intervention as ineffective because the observed effect size was neither statistically nor clinically significant. Although the threat of contamination is an issue in some controlled trials, it may be not be of much practical importance in many. Trialists should use individual randomisation if possible because of the drawbacks of cluster allocation. Cluster trials are associated with problems of recruitment bias and the need for larger samples than would be required in similar, individually randomised trials. In recruitment bias, different sorts of participants are selected into the various arms of the trial, thereby defeating the objective of randomisation, while a larger sample size may increase the cost of a trial, its length, or its complexity. This paper describes the difficulties of cluster trials and argues that the problem of contamination can often be dealt with by individual randomisation. #### Summary points Cluster trials are often used to prevent “contamination” between intervention and control groups Cluster trials are usually very much larger than individually randomised trials and can be susceptible to recruitment bias The problem of contamination can often be overcome by increasing the sample size In terms of total sample size, cluster trials are only more efficient where contamination exceeds 30% Members of clusters cannot be …

Dietary protein and bone health: a systematic review and meta-analysis

BACKGROUND There has been a resurgence of interest in the controversial relation between dietary protein and bone health. OBJECTIVE This article reports on the first systematic review and meta-analysis of the relation between protein and bone health in healthy human adults. DESIGN The MEDLINE (January 1966 to September 2007) and EMBASE (1974 to July 2008) databases were electronically searched for all relevant studies of healthy adults; studies of calcium excretion or calcium balance were excluded. RESULTS In cross-sectional surveys, all pooled r values for the relation between protein intake and bone mineral density (BMD) or bone mineral content at the main clinically relevant sites were significant and positive; protein intake explained 1-2% of BMD. A meta-analysis of randomized placebo-controlled trials indicated a significant positive influence of all protein supplementation on lumbar spine BMD but showed no association with relative risk of hip fractures. No significant effects were identified for soy protein or milk basic protein on lumbar spine BMD. CONCLUSIONS A small positive effect of protein supplementation on lumbar spine BMD in randomized placebo-controlled trials supports the positive association between protein intake and bone health found in cross-sectional surveys. However, these results were not supported by cohort study findings for hip fracture risk. Any effects found were small and had 95% CIs that were close to zero. Therefore, there is a small benefit of protein on bone health, but the benefit may not necessarily translate into reduced fracture risk in the long term.