Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60 mg/day, and 2,572 raloxifene 120 mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.

The provision of adequate analgesia and anxiolysis is an important role for emergency physicians. Despite increased awareness of this subject in the medical literature, inadequate attention to pain and anxiety in paediatric patients continues. Recent reviews 1-5 have centred on safety issues in the delivery of sedative drugs in the non-operating room setting and highlight the need for controlled trials of diVerent sedative protocols used in children in varied settings. Ketamine and midazolam are two agents commonly used for sedating children during medical procedures but despite their reported suitability for procedural sedation in the emergency department (ED) setting 1 4 5 their use remains erratic. This study aimed to compare intranasal midazolam (INM) with a combination of intravenous ketamine plus intravenous midazolam (IVKM) for sedation of children requiring minor procedures, such as laceration repair or foreign body removal, in the ambulatory setting. A comparison of these methods in this particular setting has not previously been published. The ED in this study had existing protocols for these techniques and although INM was being used more frequently than IVKM, there were concerns regarding its reliability. We hypothesised that IVKM would more reliably produce a suitable level of sedation for minor procedures than INM and that both doctors and parents would be more satisfied with this method of sedation.

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Summary. Mineral homeostasis was studied biochemically and histologically in patients in early pregnancy and at term. In early pregnancy there was evidence of increased and reversible resorption of bone, whereas in late pregnancy bone demonstrated active formation and rapid mineralization with minimal resorption. Gut absorption of calcium was not increased in early pregnancy. The overall findings were consistent with calcium liberation from bone in early pregnancy, and with enhanced conservation of bone calcium at term. It is proposed that the additional calcium required during pregnancy is derived largely from the skeleton during early gestation and from dietary absorption at term.

Conventional hormone replacement therapy preserves bone mass predominantly by reducing bone turnover but does not exert significant anabolic skeletal effects. In contrast, high doses of estrogen have been shown to increase bone formation in animals and we have recently reported high bone mineral density values in women treated long-term with estradiol implant therapy. The aim of this study was to investigate the mechanisms by which high doses of estrogen may increase bone mass in postmenopausal women. Iliac crest biopsies were obtained from 12 women who had received long-term treatment with estradiol implants (at least 14 years), on demand, following hysterectomy and bilateral salpingo-oophorectomy. Indices of bone turnover, remodeling balance and cancellous bone structure were assessed by image analysis and compared with those of premenopausal women. Mean wall width was significantly higher in women treated with estradiol therapy than in premenopausal women (44. 8 +/- 4.8 vs 38.8 +/- 2.8 mm; mean +/- SD; p = 0.001) and eroded cavity area was significantly lower in the implant-treated women (3612 +/- 956 vs 5418 +/- 1404 mm(2); p = 0.001). Bone formation rate at tissue level and activation frequency were lower in the women treated with implants, although the differences were not statistically significant. Indices of cancellous bone structure were generally similar between the two groups. These results provide the first direct evidence that high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women and indicate that these are achieved by stimulation of osteoblastic activity.