Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment.

Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population

Reproductive Risk Factors and Coronary Heart Disease in the Women’s Health Initiative Observational Study

BACKGROUND: Reproductive factors provide an early window into a woman’s coronary heart disease (CHD) risk, however their contribution to CHD risk stratification is uncertain. METHODS AND RESULTS: In the Women’s Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥ 1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C-statistic, net reclassification index (or NRI with risk categories of <5%, 5–<10%, and ≥10% 10-year risk of CHD) and integrated discriminatory index (IDI) were assessed. Among 72,982 women [n=4607 CHD events, median follow-up=12.0 (IQR=8.3–13.7) years, mean (SD) age 63.2 (7.2) years], an age-adjusted reproductive risk factor model had a C-statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C-statistic increased from 0.726 to 0.730; IDI=0.0013, p-value < 0.0001). Net reclassification for women with events was not improved (NRI events=0.007, p-value=0.18); and for women without events was marginally improved (NRI non-events=0.002, p-value=0.04) CONCLUSIONS: Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination and do not materially improve net reclassification

Reproductive Risk Factors and Coronary Heart Disease in the Women’s Health Initiative Observational Study

BackgroundReproductive factors provide an early window into a woman's coronary heart disease (CHD) risk; however, their contribution to CHD risk stratification is uncertain.Methods and resultsIn the Women's Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C statistic, net reclassification index (or net reclassification index with risk categories of &lt;5%, 5 to &lt;10%, and ≥10% 10-year risk of CHD), and integrated discriminatory index were assessed. Among 72 982 women (CHD events, n=4607; median follow-up,12.0 [interquartile range, 8.3-13.7] years; mean [standard deviation] age, 63.2 [7.2] years), an age-adjusted reproductive risk factor model had a C statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages, and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C statistic increased from 0.726 to 0.730; integrated discriminatory index, 0.0013; P&lt;0.0001). Net reclassification for women with events was not improved (net reclassification index events, 0.007; P=0.18); and, for women without events, net reclassification was marginally improved (net reclassification index nonevents, 0.002; P=0.04) CONCLUSIONS: Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination, and do not materially improve net reclassification

Efficacy of intermittent PTH in WT vs. Ts65Dn mice.

<p>Male mice (N = 6–8 per group) were given daily injections of vehicle or 30 or 80 ug/kg PTH(1–34) for 4 weeks. (<b>A</b>) BMD was measured at the beginning and end of the experiment. (open squares, WT; closed circles, Ts65Dn). Dotted lines show BMD of vehicle treated animals, dashed lines, 30 ug/kg PTH; solid lines, 80 ug/kg PTH (<b>B</b>) % bone volume/tissue volume (BV/TV), trabecular number (Tb.N.) and trabecular thickness (Tb.Th.) were determined in the tibia (open bars WT; solid bars Ts65Dn). Representative superior view of a transverse micro-CT images of the trabecular bone from the proximal tibia of representative animals in each group are shown. (<b>C</b>) Micro CT measurements of the effects of PTH treatment on cortical thickness, periosteal perimeter and endocortical perimeter in the distal tibia were performed (open bars WT; solid bars Ts65Dn). *, p<0.05 vs. respective vehicle control; #, p<0.05 vs. WT vehicle.</p

Histomorphometric measurement of bone formation and bone resorption following intermittent PTH in WT and Ts65Dn mice.

<p>Male mice (N = 6–8 per group) were given daily injections of vehicle or 30 or 80 ug/kg PTH(1–34) for 4 weeks. (<b>A</b>) Mineral apposition rate (MAR) (um³/um²/day), (<b>B</b>) Bone formation rate/bone surface (BFR/BS) (um³/um²/day), (<b>C</b>) Number of osteoblasts/bone perimeter (N.Ob./B.Pm), (<b>D</b>) Number of osteoclasts/bone perimeter (N.Oc./B.Pm.) were measured in WT and Ts65Dn mice vehicle or PTH treated (30 or 80 ug/kg/day) (open bars, WT; closed bars, Ts65Dn). *, p<0.05 vs. respective vehicle control; #, p<0.05 vs. WT vehicle.</p

Osteoclast and osteoblast formation is significantly decreased in 3 month old Ts65Dn Mice.

<p>(<b>A</b>) <i>Ex vivo</i> recruitment into the osteoblast lineage was measured at culture day 10 by staining for alkaline phosphatase (AP) and counting the number of AP+ colony forming units (CFU-F) per well. (<b>B</b>) <i>Ex vivo</i> osteoblast differentiation was assessed at culture day 28 by staining mineralized bone nodules containing differentiated colonies of osteoblasts (CFU-OB) with Alizarin Red and the number of CFU-OB per well enumerated. (<b>C</b>) <i>Ex Vivo</i> osteoclast differentiation was assessed by staining on day 14 for tartrate resistant acid phosphatase (TRAP) and the number of TRAP+-multinucleated cells per well counted. *, p<0.05 vs. WT vehicle control.</p