Context: Intravenous aminobisphosphonates often cause an acute-phase response (APR), but the precise components of this, its frequency, and the risk factors for its development have not been ...systematically studied.
Objective: The objective of the study was to characterize the APR and determine its frequency and the risk factors for its development.
Design: The study was an analysis of adverse events from a large randomized trial.
Setting: This was a multicenter international trial.
Patients: Patients included 7765 postmenopausal women with osteoporosis.
Intervention: Zoledronic acid 5 mg annually or placebo was the intervention.
Main Outcome Measure: Adverse events occurring within 3 d of zoledronic acid infusion were measured.
Results: More than 30 adverse events were significantly more common in the zoledronic acid group and were regarded collectively as constituting an APR. These were clustered into five groups: fever; musculoskeletal (pain and joint swelling); gastrointestinal (abdominal pain, vomiting, diarrhea); eye inflammation; and general (including fatigue, nasopharyngitis, edema). A total of 42.4% of the zoledronic acid group had an APR after the first infusion, compared with 11.7% of the placebo group. All APR components had their peak onset within 1 d, the median duration of the APR was 3 d, and severity was rated as mild or moderate in 90%. Stepwise regression showed that APR was more common in non-Japanese Asians, younger subjects, and nonsteroidal antiinflammatory drug users and was less common in smokers, patients with diabetes, previous users of oral bisphosphonates, and Latin Americans (P < 0.05 for all).
Conclusion: This analysis identifies new components of the APR and provides the first assessment of risk factors for it. Despite its frequency, APR rarely resulted in treatment discontinuation in this study.
The adverse event profile following infusion of zoledronic acid, novel components of the acute phase response, and risk factors for its occurrence are described.
To determine postnatal changes in plasma and interstitial glucose concentrations of healthy infants receiving current recommended care and to compare the incidence of low concentrations with ...recommended thresholds for treatment of at-risk infants.
A prospective masked observational study in Hamilton, New Zealand. Healthy, term, appropriately grown singletons had continuous glucose monitoring and repeated heel-prick plasma glucose measurements (4 in the first 24 hours then twice daily using the glucose oxidase method) from birth to 120 hours.
The 67 infants had a mean birth weight of 3584 ± 349 g, and gestational age of 40.1 ± 1.2 weeks. The mean glucose concentrations increased over the first 18 hours, remained stable to 48 hours (59 ± 11 mg/dL; 3.3 ± 0.6 mmol/L) before increasing to a new plateau by the fourth day (89 ± 13 mg/dL; 4.6 ± 0.7 mmol/L). Plasma glucose concentrations of 47 mg/dL (2.6 mmol/L) approximated the 10th percentile in the first 48 hours, and 39% of infants had ≥1 episode below this threshold. Early term infants had lower mean glucose concentrations than those born at later gestational ages and were more likely to have episodes <47 mg/dL (<2.6 mmol/L) (19/32 59% vs 7/35 20%; relative risk, 3.0; 95% CI, 1.4-6.1; P = .001).
Healthy infants seem to complete their metabolic transition by day 4. Many have glucose concentrations below the accepted thresholds for treatment of hypoglycemia.
ACTRN: 12615000986572.
Vitamin D insufficiency is associated with many disorders, leading to calls for widespread supplementation. Some investigators suggest that more clinical trials to test the effect of vitamin D on ...disorders are needed.
We did a trial sequential meta-analysis of existing randomised controlled trials of vitamin D supplements, with or without calcium, to investigate the possible effect of future trials on current knowledge. We estimated the effects of vitamin D supplementation on myocardial infarction or ischaemic heart disease, stroke or cerebrovascular disease, cancer, total fracture, hip fracture, and mortality in trial sequential analyses using a risk reduction threshold of 5% for mortality and 15% for other endpoints.
The effect estimate for vitamin D supplementation with or without calcium for myocardial infarction or ischaemic heart disease (nine trials, 48 647 patients), stroke or cerebrovascular disease (eight trials 46 431 patients), cancer (seven trials, 48 167 patients), and total fracture (22 trials, 76 497 patients) lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk of any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 trials, 27 834 patients). Vitamin D co-administered with calcium reduced hip fracture in institutionalised individuals (two trials, 3853 patients) but did not alter the relative risk of hip fracture by 15% or more in community-dwelling individuals (seven trials, 46 237 patients). There is uncertainty as to whether vitamin D with or without calcium reduces the risk of death (38 trials, 81 173).
Our findings suggest that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions.
Health Research Council of New Zealand.
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 (n = 602, 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 (n = 127), we found a nonsignificant increase in COPD prevalence following diagnosis (56-61%; p = 0.45). 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.
Associations between serum calcium and vascular disease have been reported, but the consistency of these findings is unknown. We conducted a systematic review to determine whether circulating calcium ...concentrations are associated with risks of cardiovascular disease and death in normocalcaemic populations. We conducted PubMed searches up to 18 December 2014 and scrutinized reference lists of papers. Eligible studies related serum calcium to mortality or cardiovascular events in humans. A follow‐up of at least one year was required for longitudinal studies. Studies in populations selected on the basis of renal disease or abnormal serum calcium were excluded. Two investigators performed independent data extraction. The results were tabulated and, where possible, meta‐analysed. Five of 11 studies reported a statistically significant positive association between serum calcium and mortality. Meta‐analysis of eight of these studies showed a hazard ratio of death of 1.13 (1.09, 1.18) per standard deviation of serum calcium. Eight of 13 studies reported a statistically significant positive association between serum calcium and cardiovascular disease. Meta‐analysis of eight studies showed a hazard ratio of cardiovascular disease of 1.08 (1.04, 1.13) per standard deviation of serum calcium. For two studies reporting odds ratios, the pooled odds ratio per standard deviation was 1.22 (1.11, 1.32). When hazard ratios adjusted for cardiovascular risk factors were meta‐analysed, the pooled hazard ratio was 1.04 (1.01, 1.08). Other studies demonstrated associations between serum calcium and stroke and between serum calcium and direct measurements of arterial disease and calcification. These observational data indicate that serum calcium is associated with vascular disease and death, but they cannot determine causality.
BACKGROUND:Statistical techniques can investigate data integrity in randomized controlled trials (RCTs). We systematically reviewed and analyzed all human RCTs undertaken by a group of researchers, ...about which concerns have been raised.
METHODS:We compared observed distributions of p values for between-groups differences in baseline variables, for standardized sample means for continuous baseline variables, and for differences in treatment group participant numbers with the expected distributions. We assessed productivity, recruitment rates, outcome data, textual consistency, and ethical oversight.
RESULTS:The researchers were remarkably productive, publishing 33 RCTs over 15 years involving large numbers of older patients with substantial comorbidity, recruited over very short periods. Treatment groups were improbably similar. The distribution of p values for differences in baseline characteristics differed markedly from the expected uniform distribution (p = 5.2 × 10). The distribution of standardized sample means for baseline continuous variables and the differences between participant numbers in randomized groups also differed markedly from the expected distributions (p = 4.3 × 10, p = 1.5 × 10, respectively). Outcomes were remarkably positive, with very low mortality and study withdrawals despite substantial comorbidity. There were very large reductions in hip fracture incidence, regardless of intervention (relative risk 0.22, 95% confidence interval 0.15–0.31, p < 0.0001, range of relative risk 0.10–0.33), that greatly exceed those reported in meta-analyses of other trials. There were multiple examples of inconsistencies between and within trials, errors in reported data, misleading text, duplicated data and text, and uncertainties about ethical oversight.
CONCLUSIONS:A systematic approach using statistical techniques to assess randomization outcomes can evaluate data integrity, in this case suggesting these RCT results may be unreliable.
ObjectiveFormal 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 ...meta-analysis of mortality studies in acromegaly has thus been performed to assess the effect of lowering serum GH and IGF-I on survival.Design and methodsMedline was searched for studies under ‘acromegaly’, ‘mortality’ and ‘cause of death’ (1965–2008), and 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).ResultsPatients with random serum GH <2.5 μg/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 >2.5 μg/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 (>70%) rates of biochemical remission after treatment.ConclusionsClinicians treating acromegalic patients should aim for random serum GH <2.5 μg/l measured by RIA (probably <1 μg/l measured by modern sensitive immunoassay) and normal serum IGF-I values, to restore the elevated mortality of the condition to normal levels.
Background The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. Methods We analysed ...DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). Results DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. Conclusions Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.
Frequent use of personal, nonprotocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D (CaD) on cardiovascular risk in the Women's Health Initiative (WHI).
We ...investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study (WHI CaD) by using the WHI limited-access clinical trials data set.
The WHI CaD was a 7-y, randomized, placebo-controlled trial of CaD (1 g Ca/400 IU vitamin D daily) in 36,282 community-dwelling, postmenopausal women. The incidence of total cancer (excluding nonmelanoma skin cancers), breast and colorectal cancers, hip and total fracture, and mortality was assessed by using Cox proportional hazards models.
In the WHI CaD, interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total, breast, and colorectal cancers but not for fracture or mortality. In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).
For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and colorectal cancers and did not change the risk of fractures or total mortality. The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements. The WHI CaD trial is registered at clinicaltrials.gov as NCT00000611.
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