Objective To investigate whether calcium supplements increase the risk of cardiovascular events.Design Patient level and trial level meta-analyses.Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010.Study selection Eligible studies were randomised, placebo controlled trials of calcium supplements (≥500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates.Results 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038).Conclusions Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

Objectives To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women's Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk. Design Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36 282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data. Results In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P=0.04), stroke (1.20 (1.00 to 1.43), P=0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P=0.02). In metaanalyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28 072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).Conclusions Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

Chronic obstructive pulmonary disease (COPD) is a common comorbid disease in lung cancer, estimated to affect 40-70% of lung cancer patients, depending on diagnostic criteria. As smoking exposure is found in 85-90% of those diagnosed with either COPD or lung cancer, coexisting disease could merely reflect a shared smoking exposure. Potential confounding by age, sex and pack-yr smoking history, and/or by the possible effects of lung cancer on spirometry, may result in over-diagnosis of COPD prevalence.In the present study, the prevalence of COPD (pre-bronchodilator Global Initiative for Chronic Obstructive Lung Disease 2+ criteria) in patients diagnosed with lung cancer was 50% compared with 8% in a randomly recruited community control group, matched for age, sex and pack-yr smoking exposure (n5602, odds ratio 11.6; p,0.0001).In a subgroup analysis of those with lung cancer and lung function measured prior to the diagnosis of lung cancer (n5127), we found a nonsignificant increase in COPD prevalence following diagnosis (56-61%; p50.45). After controlling for important variables, the prevalence of COPD in newly diagnosed lung cancer cases was six-fold greater than in matched smokers; this is much greater than previously reported.We conclude that COPD is both a common and important independent risk factor for lung cancer.KEYWORDS: Chronic obstructive pulmonary disease, epidemiology, lung cancer, risk, spirometry A s only 10-15% of chronic smokers get lung cancer [1], host susceptibility factors have been implicated. Age, smoking history, family history and impaired lung function have been identified as key risk factors [2]. The question that then arises is: does the association between chronic obstructive pulmonary disease (COPD) and lung cancer come down to more than a shared smoking history?Cross-sectional studies show that the prevalence of COPD is 40-70% of those diagnosed with lung cancer [3,4], although prevalence is highly dependent on diagnostic criteria, age, sex and smoking exposure [5]. As none of these studies compared the prevalence of COPD in their lung cancer cohorts with a smoking cohort matched for these variables, the significance of this finding is uncertain. Moreover, none of these studies considered that lung cancer may itself cause an obstructive effect on spirometry. It is possible that potential confounding by age, sex and packyr smoking history on COPD prevalence, and/or the possible effects of lung cancer per se on spirometry, could result in over-diagnosis of COPD and a falsely increased association between COPD and lung cancer.

Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 +/- 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9-3.6) in those with last follow-up GH greater than 5 microg/liter to 2.5 (1.6-3.8), 1.6 (0.9-3), and 1.1 (0.5-2.1) for those with GH less than 5, less than 2, and less than 1 microg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an SD score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8-4.2) for those with an SD score greater than 2, 1.6 (0.6-2.6) for those with an SD score less than 2 (normal or low levels), and 1.0 (0.1-3) for those with an SD score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I SD score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels.

Objective: Formal studies of acromegaly have found increased mortality associated with the disorder, although reduction of serum levels of GH and IGF-I by treatment appears to improve survival. A metaanalysis of mortality studies in acromegaly has thus been performed to assess the effect of lowering serum GH and IGF-I on survival. Design and methods: Medline was searched for studies under 'acromegaly', 'mortality' and 'cause of death ' (1965-2008), and abstracts of recent meetings of the US Endocrine Society were hand searched. Studies were restricted to those presenting mortality data according to serum GH and IGF-I at last follow-up, and with mortality expressed as a standardized mortality ratio (SMR). Results: Patients with random serum GH !2.5 mg/l following treatment, mostly measured by standard RIA, had mortality close to expected levels (SMR 1.1, 95% confidence interval (CI) 0.9-1.4) compared with an SMR of 1.9 (95% CI 1.5-2.4) for those with final GH O2.5 mg/l. Similarly, a normal serum IGF-I for age and sex at last follow-up after treatment was associated with an SMR of 1.1 (95% CI 0.9-1.4) compared with an SMR of 2.5 (95% CI 1.6-4.0) for those with continued IGF-I elevation. There was a significant trend for reduced mortality in series reporting frequent use of somatostatin analogues and in studies reporting high (O70%) rates of biochemical remission after treatment. Conclusions: Clinicians treating acromegalic patients should aim for random serum GH !2.5 mg/l measured by RIA (probably !1 mg/l measured by modern sensitive immunoassay) and normal serum IGF-I values, to restore the elevated mortality of the condition to normal levels. European Journal of Endocrinology 159 89-95