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Objective To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.Design Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses.Data sources Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014.Eligibility criteria for selecting studies Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50.Results There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58 573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48 967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56 648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51 775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger’s regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44 505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.Conclusions Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.

The role for ultrasound (US) in the assessment of nodular thyroid disease has increased in recent years. This expanded role has been highlighted in recent consensus guidelines on the management of nodular thyroid disease. In this review, we address the potential roles for US in assessing thyroid nodules and review these recent guidelines. In particular, we review the evidence that US characteristics of thyroid nodules can predict the risk of malignancy. A predominantly solid nodule, hypoechogenicity, microcalcification, macrocalcification, ill-defined margins, intranodular vascularity, and taller-than-wide shape have all been associated with increased risk of malignancy, but no single US characteristic is sufficiently sensitive or specific to exclude or diagnose malignancy by itself. However, the use of combinations of US characteristics to stratify nodules into high and low risk for malignancy appears a promising strategy. Unselected nodules without any suspicious US features have a low risk of malignancy (<2%), whereas malignancy rates are much higher in nodules with at least two suspicious features. Recent guidelines endorse this approach of using combinations of US features to guide nodule selection for fine needle aspiration.

We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between −1.0 and −2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints.

These results confirm the secular trend of Paget's disease presenting later in life and in milder form, suggesting that there are important environmental determinants. The relatively few 'incident' cases are mostly in the very elderly. Given the secular trend and limitations to life expectancy, it is predicted that Paget's disease will become increasingly rare.