Establishing a reference range for bone turnover markers in young, healthy women.

INTRODUCTION: Biochemical markers of bone turnover (BTMs) are important in determining fracture risk in postmenopausal women; high levels being associated with increased risk. A proposed goal of anti-resorptive therapy is to reduce BTMs to the lower half of the reference range for healthy young pre-menopausal women. Our aims were a) to establish reference ranges for bone alkaline phosphatase (bone ALP), crosslinked C- and N-telopeptides of type I collagen (betaCTX, NTX), osteocalcin (OC) and procollagen type I N propeptide (PINP) in pre-menopausal women and b) to investigate the determinants of these BTMs. METHODS: BTMs were measured in peripheral blood and second morning void urine collected from 200 healthy pre-menopausal women ages 30 to 45 years. Each subject completed a short medical and lifestyle questionnaire. RESULTS: BTMs were higher before the age of 35 years than after it. BTMs were higher in women with low BMI (betaCTX and OC), low alcohol consumption (PINP), current smoking habit (bone ALP and NTX), and around time of ovulation (NTX). CONCLUSIONS: We recommend that the age range 35 to 45 years should be used when establishing BTM reference ranges in women.

Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease.

BACKGROUND AND PURPOSE: There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. MATERIALS AND METHODS: Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret- CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. RESULTS: Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret-. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret- group were normal, and none of the abnormalities noted were more prevalent in controls. CONCLUSIONS: Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment.

A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy.

Lasofoxifene is a novel selective estrogen receptor modulator that is being developed for the treatment of postmenopausal osteoporosis. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is currently used to diagnose osteoporosis. BMD response to therapy, however, is often not apparent until at least one year following start of treatment. Biochemical markers of bone turnover may provide an early indication of BMD response in individual patients. The aims of the study were: 1) to determine the variability in bone turnover markers (BTM) to estimate a value for least significant change (LSC); 2) to determine the number of subjects with a response to lasofoxifene greater than LSC; 3) to determine the number of subjects whose bone turnover is decreased to the lower half of the reference range and 4) to evaluate the use of bone turnover markers to predict the change in bone density in response to lasofoxifene. Fifty-one postmenopausal osteopenic women, ages 55 to 77 (mean 63.7) years, were recruited with 44 women completing the 2 year follow up. Participants received either lasofoxifene (0.25 mg/d) or placebo, in a 1:1 ratio. Duplicate measurements of BTM (bone alkaline phosphatase (bone ALP), N-terminal propeptide of type I collagen (PINP), serum beta crosslinked C-telopeptides of type I collagen (sbeta-CTX), urinary crosslinked N-telopeptides of type I collagen (U-NTX)) were made at baseline and 6 months with single measurements at 4, 8 and 12 weeks. Duplicate measurements of BMD at the lumbar spine (LS), total hip (TH) and distal forearm (DF) were made by DXA at baseline, one and two years in all subjects. Almost all women (92 to 96%), treated with lasofoxifene, had a reduction in serum-based bone turnover markers greater than LSC, and 52 to 80% had serum-based bone turnover markers in the lower half of the reference range, by six months of lasofoxifene therapy. The change in mean LSBMD from baseline, was significantly greater in the lasofoxifene group compared to placebo at 1 and 2 years (+2.5% and +3.4%, respectively, P<0.0001). Change in PINP and U-NTX at 6 months correlated inversely with change in LS and TH BMD at one and two years. The use of lasofoxifene therapy leads to significant decreases in bone turnover by 4 weeks of lasofoxifene therapy as a group, with a decrease in BTM greater than LSC occurring in almost all women taking lasofoxifene by 6 months. By this time, in over half of women taking lasofoxifene, BTM reached the lower half of the reference range. Our results suggest that bone turnover markers are useful for monitoring response to lasofoxifene. Changes occur early and relate to the BMD response.

Ethical and legal issues regarding selective abortion of fetuses with Down syndrome.

Selective abortion of fetuses with Down syndrome was discussed in terms of current abortion perspectives, genetic testing, legislation, and ethical principles. Legal doctrine and practice were presented in terms of the disparate treatment given the fetus with Down syndrome as compared to the fetus with no apparent disabilities. Finally, the ethical principles of autonomy, beneficence, nonmaleficence, fidelity, and justice were offered as guidelines for the examination of the legal double standards imposed by current legislation.