Longitudinal assessment of in vivo bone dynamics in a mouse tail model of postmenopausal osteoporosis.

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (µCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6 mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6 mice were ovariectomized (OVX, n = 11) or sham-operated (SHM, n = 9) and monitored with in vivo µCT on the day of surgery and every 2 weeks after, up to 12 weeks. There was a significant decrease in bone volume fraction for OVX (-35%) compared to SHM (+16%) in trabecular bone (P < 0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P < 0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (-16%) compared to SHM (+11%, P < 0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P < 0.001) and a delayed increase in bone formation rate (P < 0.001). Monitoring transient bone biology is a promising method for future research.

Bone adaptation to cyclic loading in murine caudal vertebrae is maintained with age and directly correlated to the local micromechanical environment.

The ability of the skeleton to adapt to mechanical stimuli (mechanosensitivity) has most often been investigated at the whole-bone level, but less is known about the local mechanoregulation of bone remodeling at the bone surface, especially in context of the aging skeleton. The aim of this study was to determine the local and global mechanosensitivity of the sixth caudal vertebra during cyclic loading (8 N, three times per week, for six weeks) in mice aged 15, 52, and 82 weeks at the start of loading. Bone adaptation was monitored with in vivo micro-computed tomography. Strain energy density (SED), assumed as the mechanical stimulus for bone adaptation, was determined with micro-finite element models. Mechanical loading had a beneficial effect on the bone microstructure and bone stiffness in all age groups. Mineralizing surface was on average 13% greater (p<0.05) in loaded than control groups in 15- and 82-week-old mice, but not for 52-week-old mice. SED at the start of loading correlated to the change in bone volume fraction in the following 6 weeks for loaded groups (r(2)=0.69-0.85) but not control groups. At the local level, SED was 14-20% greater (p<0.01) at sites of bone formation, and 15-20% lower (p<0.01) at sites of bone resorption compared to quiescent bone surfaces for all age groups, indicating SED was a stimulus for bone adaptation. Taken together, these results support that mechanosensitivity is maintained with age in caudal vertebrae of mice at a local and global level. Since age-related bone loss was not observed in caudal vertebrae, results from the current study might not be translatable to aged humans.

A double-blind comparison of olanzapine versus risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities.

BACKGROUND: In addition to demonstrating their superiority to placebo, there is a need to compare the relative efficacy and side effects of atypical neuroleptics for the acute treatment of dementia-related behavioral disturbances in residents of long-term care facilities. METHOD: In a double-blind parallel study allowing dose titration over 14 days, 39 agitated persons with DSM-IV dementia who were residing in long-term care facilities were administered olanzapine (N = 20) or risperidone (N = 19) as acute treatment. Drug was administered once a day at bedtime. The initial dosages were olanzapine, 2.5 mg/day, and risperidone, 0.5 mg/day. Titration was allowed to maximum doses of olanzapine, 10 mg/day, and risperidone, 2.0 mg/day. The primary outcome measures were the Clinical Global Impressions scale (CGI) and the Neuropsychiatric Inventory (NPI). Data were gathered from 2000 to 2002. RESULTS: Both drugs produced significant reductions in CGI and NPI scores (p <.0001), but there was no significant difference between drugs. The mean olanzapine dose was 6.65 mg/day; for risperidone, the dose was 1.47 mg/day. The positive drug effect was not accompanied by decreased mobility, and there was improvement on a quality-of-life measure. The chief adverse events were drowsiness and falls. At baseline, 42% (16/38) of subjects in both groups had extrapyramidal symptoms that increased slightly, but not significantly, by the end of the study. CONCLUSION: Low-dose, once-a-day olanzapine and risperidone appear to be equally safe and equally effective in the treatment of dementia-related behavioral disturbances in residents of extended care facilities.

Trabecular bone adapts to long-term cyclic loading by increasing stiffness and normalization of dynamic morphometric rates.

Bone has the ability to adapt to external loading conditions. Especially the beneficial effect of short-term cyclic loading has been investigated in a number of in vivo animal studies. The aim of this study was to assess the long-term effect (>10 weeks) of cyclic mechanical loading on the bone microstructure, bone stiffness, and bone remodeling rates. Mice were subjected to cyclic mechanical loading at the sixth caudal vertebra with 8N or 0N (control) three times per week for a total period of 14 weeks. Structural bone parameters were determined from in vivo micro-computed tomography (micro-CT) scans performed at week 0, 4, 6, 8, 10, 12, and 14. Mechanical parameters were derived from micro-finite element analysis. Dynamic bone morphometry was calculated using registration of serial micro-CT scans. Bone volume fraction and trabecular thickness increased significantly more for the loaded group than for the control group (p = 0.006 and p = 0.002 respectively). The trabecular bone microstructure adapted to the load of 8N in approximately ten weeks, indicated by the trabecular bone volume fraction, which increased from 16.7% at 0 weeks to 21.6% at week 10 and only showed little change afterwards (bone volume fraction of 21.5% at 14 weeks). Similarly bone stiffness - (at the start of the experiment 649N/mm) - reached 846N/mm at 10 weeks in the loaded group and was maintained to the end of the experiment (850N/mm). At 4 weeks the bone formation rate was 32% greater and the bone resorption rate 22% less for 8N compared to 0N. This difference was significantly reduced as the bone adapted to 8N, with 8N remodeling rates returning to the values of the 0N group at approximately 10 weeks. Together these data suggest that once bone has adapted to a new loading state, the remodeling rates reduce gradually while maintaining bone volume fraction and stiffness.

Impact of an activities-based adult dementia care program.

The investigators studied over one year the impact of a newly established once-a-week activity-based day care program for dementia patients combined with 17 educational sessions for caregivers held at the same facility. Outcome measures were patient and caregiver quality of life (QOL), patient behavioral disturbance, and use of community-based resources. Of the 37 enrollees, 3 chose not to start the program and 13 dropped out before the end of one year, largely due to health-related issues. Of the initial group, 21 attended for the entire year. The average patient Mini-Mental State Exam (MMSE) score at entry was 16, indicating a moderate level of dementia. Average score on the CERAD Behavior Rating Scale for Dementia (BRSD) was 30.1, indicating a mild level of behavioral disturbance. Attendance at day care was 91%; at the caregiver educational sessions, 74%. Patient and caregiver enthusiasm for the program was high and all wanted to continue attendance beyond the study period despite the fact that patients reported no change in QOL. Caregivers rated patients as having significantly less QOL, and rated their own QOL as unchanged. Symptomatic patient behaviors, as measured by the BRSD, increased significantly over the period of study. Caregivers reported greater use of community resources.

Responsiveness of the quality of life in late-stage dementia scale to psychotropic drug treatment in late-stage dementia.

BACKGROUND: We report on the responsiveness of a previously validated quality-of-life scale, the Quality of Life in Late-Stage Dementia scale (QUALID), as an outcome measure in a clinical trial of two psychotropic medications. METHODS: Secondary analyses were conducted comparing outcome measures used in a randomized double-blind trial of two antipsychotics (olanzapine and risperidone) for the treatment of dementia-related behavioral symptoms. The QUALID was completed for 31 of the patients in addition to several measures of behavior-related dementia symptoms including the Neuropsychiatric Inventory, the Withdrawn Behavior subscale of the Multidimensional Observation Scale for Elderly Subjects, the Mini-Mental State Examination, and the Clinical Global Impression. Measures of safety and adverse effects included the Simpson-Angus Scale and records of specific adverse events. RESULTS: A significant positive relationship was found between QUALID score and improvement in behavioral symptoms, and a negative association was found with adverse medication effects. CONCLUSIONS: The QUALID was sensitive to both the treatment effects and the adverse effects of medication in this sample of patients.