No abstract

Increased bone turnover has been suggested as a potential risk factor for osteoporotic fractures. We investigated this hypothesis in a prospective cohort study performed on 7598 healthy women more than 75 years of age. One hundred and twenty-six women (mean years 82.5) who sustained a hip fracture during a mean 22-month follow-up were age-matched with three controls who did not fracture. Baseline samples were collected prior to fracture for the measurement of two markers of bone formation and three urinary markers of bone resorption: type I collagen cross-linked N- (NTX) or C-telopeptide (CTX) and free deoxypyridinoline (free D-Pyr). Elderly women had increased bone formation and resorption compared with healthy premenopausal women. Urinary excretion of CTX and free D-Pyr, but not other markers, was higher in patients with hip fracture than in age-matched controls (p = 0.02 and 0.005, respectively). CTX and free D-Pyr excretion above the upper limit of the premenopausal range was associated with an increased hip fracture risk with an odds ratio (95% confidence interval) of 2.2 (1.3-3.6) and 1.9 (1.1-3.2), respectively, while markers of formation were not. Increased bone resorption predicted hip fracture independently of bone mass, i.e., after adjustment for femoral neck bone mineral density (BMD) and independently of mobility status assessed by the gait speed. Women with both a femoral BMD value of 2.5 SD or more below the mean of young adults and either high CTX or high free D-Pyr levels were at greater risk of hip fracture, with an odds ratio of 4.8 and 4.1, respectively, than those with only low BMD or high bone resorption. Elderly women are characterized by increased bone turnover, and some markers of bone resorption predict the subsequent risk of hip fracture independently of hip BMD. Combining the measurement of BMD and bone resorption may be useful to improve the assessment of the risk of hip fracture in elderly women.

We conducted a population-based cohort study in 7598 white healthy women, aged 75 years and over, recruited from the voting lists. We measured at baseline bone mineral density (BMD g/cm2) of the proximal femur (neck, trochanter and Ward's triangle) and the whole body, as well as fat and lean body mass, by dual-energy X-ray absorptiometry (DXA). One hundred and fifty-four women underwent a hip fracture during an average 2 years follow-up. Each standard deviation decrease in BMD increased the risk of hip fracture adjusted for age, weight and centre by 1.9 (95% CL 1.5, 2.3) for the femoral neck, 2.6 times (2.0, 3.3) for the trochanter, 1.8 times (1.4, 2.2) for Ward's triangle, 1.6 times (1.2, 2.0) for the whole body, and 1.3 times (1.0, 1.5) for the fat mass. The areas under the receiver operating characteristic (ROC) curves were not significantly different between trochanter and femoral neck BMD, whereas ROC curves of femoral neck and trochanter BMD were significantly better than those for Ward's triangle and whole-body BMD. Women who sustained an intertrochanteric fracture were older (84 +/- 4.5 years) than women who had a cervical fracture (81 +/- 4.5 years) and trochanter BMD seemed to be a stronger predictor of intertrochanteric ([RR = 4.5 (3.1, 6.5)] than cervical fractures ([RR = 1.8 (1.5, 2.3]). In very elderly women aged 80 years and more, hip BMD was still a significant predictor of hip fracture but the relative risk was significantly lower than in women younger than 80 years. In the 48% of women who had a femoral neck BMD T-score less than -2.5, the relative risk of hip fracture was increased by 3, and the unadjusted incidence of hip fracture was 16.4 per 1000 woman-years compared with 1.1 in the population with a femoral neck BMD T-score > or = -1.

Objective. This study was undertaken to assess the effect of strontium ranelate on nonvertebral and vertebral fractures in postmenopausal women with osteoporosis in a 5-year, double-blind, placebo-controlled trial. Methods.A total of 5,091 postmenopausal women with osteoporosis were randomized to receive either strontium ranelate at 2 gm/day or placebo for 5 years. The main efficacy criterion was the incidence of nonvertebral fractures. In addition, incidence of hip fractures was assessed, by post hoc analysis, in the subset of 1,128 patients who were at high risk of fractures (age 74 years or older with lumbar spine and femoral neck bone mineral density T scores ؊2.4 or less). The incidence of new vertebral fractures was assessed, using the semiquantitative method described by Genant, in the 3,646 patients in whom spinal radiography (a nonmandatory procedure) was performed during the course of the study. Fracture data were analyzed using the KaplanMeier survival method.Results. Of the 5,091 patients, 2,714 (53%) completed the study up to 5 years. The risk of nonvertebral Supported by Servier.

Little is known about the molecular mechanism(s) governing differentiation decisions in embryonic stem cells (ESCs). To identify factors critical for ESC lineage formation, we carried out a functional genetic screen for factors affecting Nanog promoter activity during mESC differentiation. We report that members of the PBAF chromatin remodeling complex, including Smarca4/Brg1, Smarcb1/ Baf47, Smarcc1/Baf155, and Smarce1/Baf57, are required for the repression of Nanog and other self-renewal gene expression upon mouse ESC (mESC) differentiation. Knockdown of Smarcc1 or Smarce1 suppressed loss of Nanog expression in multiple forms of differentiation. This effect occurred in the absence of self-renewal factors normally required for Nanog expression (e.g., Oct4), possibly indicating that changes in chromatin structure, rather than loss of self-renewal gene transcription per se, trigger differentiation. Consistent with this notion, mechanistic studies demonstrated that expression of Smarcc1 is necessary for heterochromatin formation and chromatin compaction during differentiation. Collectively, our data reveal that Smarcc1 plays important roles in facilitating mESCs differentiation by coupling gene repression with global and local changes in chromatin structure.