Abstract Introduction and hypothesis: Diagnosis of prevalent osteoporotic vertebral fracture is complicated by normal or developmental variation in vertebral shape or size and non-osteoporotic ...deformities that appear to have ‘reduced’ height. Using our visual approach, the algorithm-based qualitative method (ABQ) a vertebra with apparent “reduced” height without evidence of osteoporotic endplate depression is classified as non-osteoporotic short vertebral height (SVH). We aimed to determine whether ABQ classification of SVH represents true or false negative diagnosis of osteoporotic vertebral fracture, by testing the associations with clinical outcomes of osteoporosis or vertebral fracture. Methods: The ABQ method was used to assess spinal radiographs acquired at baseline for a subset of 904 postmenopausal women participating in the Osteoporosis and Ultrasound Study (OPUS). The sample was enriched with vertebral fracture cases. Subjects were categorized by ABQ diagnosis as (i) normal, (ii) non-osteoporotic short vertebral height (SVH) or (iii) osteoporotic vertebral fracture. Results: Women were classified by ABQ as follows: osteoporotic vertebral fracture, n = 231; SVH, n = 376 and normal, n = 297. Women with vertebral fracture were older, with lower height, weight and height loss than those classified as SVH or normal. Women with SVH were heavier and older, with greater historical height loss than normal women. Age-adjusted SD units ( z -scores) for BMD were lower than expected among women with osteoporotic vertebral fracture, but not among those with SVH. There was a significant association between diagnosis of osteoporotic vertebral fracture and history of low-trauma non-vertebral and vertebral fracture ( p < 0.001, odds ratios = 3.2 and 20.6, respectively). There was also an association between diagnosis of SVH and previous low-trauma non-vertebral fracture ( p < 0.05, odds ratio = 1.7). Conclusions: Short vertebral height without evidence of central endplate fracture in postmenopausal women is largely unrelated to osteoporosis. Quantitative morphometry should not be used alone for the assessment of vertebral fracture in clinical decision making: we recommend differential diagnosis of morphometric vertebral deformities by an expert reader to rule out non-osteoporotic deformities with short vertebral height.
Summary
We observed similar prevalence of short vertebral height without endplate depression (SVH) in young women aged 20–39 years and older women aged 55–79 years. There was no association between ...SVH and low bone density. In older women, therefore, SVH may be largely long standing and not indicative of osteoporotic fracture.
Introduction
Algorithm-based qualitative (ABQ) definition of osteoporotic vertebral fracture (VF) requires evidence of endplate fracture, and there is no minimum threshold for apparent ‘reduction’ in vertebral height. In older women, SVH without endplate fracture identified on baseline assessment may be long standing and unrelated to VF. If this is so, we would expect to see a similar prevalence of SVH in younger women. We aimed to compare the prevalence of pre- and postmenopausal women with SVH and the characteristics of women with and without SVH.
Methods
We used the ABQ method to classify baseline vertebral images (DXA-based imaging) from 257 premenopausal and 1,361 postmenopausal women participating in the population-based Osteoporosis and Ultrasound Study. Images were classified as follows: normal (no VF, no SVH), SVH (no VF) or VF (with/without SVH in unfractured vertebrae). We compared proportions of women with SVH (chi-squared test) and compared age, height, weight and bone mineral density (BMD) by ABQ classification (two-sample
t
test/analysis of variance).
Results
The prevalence of pre- and postmenopausal women with SVH was 37% and 33%, respectively (
P
>0.05). Compared to women without SVH, premenopausal women with SVH were older (
P
<0.001) and heavier (
P
=0.05), and postmenopausal women with SVH were taller (
P
<0.05), with higher spine BMD (
P
<0.01). Postmenopausal women with VF were older (
P
<0.001) and shorter (
P
<0.01) with lower BMD (
P
<0.001) than women without VF.
Conclusions
Short vertebral height without endplate fracture is equally prevalent in pre- and postmenopausal women and not associated with low bone density.
Bone development is dependent on the functionality of three essential cell types: chondrocytes, osteoclasts and osteoblasts. If any of these cell types is dysfunctional, a developmental bone ...phenotype can result.
The bone disease osteopetrosis is caused by osteoclast dysfunction or impaired osteoclastogenesis, leading to increased bone mass. In ClC-7 deficient mice, which display severe osteopetrosis, the osteoclast malfunction is due to abrogated acidification of the resorption lacuna. This study sought to investigate the consequences of osteoclast malfunction on bone development, bone structure and bone modeling/remodeling in ClC-7 deficient mice. Bones from wildtype, heterozygous and ClC-7 deficient mice were examined by bone histomorphometry and immunohistochemistry.
ClC-7 deficient mice were found to have a severe developmental bone phenotype, characterized by dramatically increased bone mass, a high content of cartilage remnants, impaired longitudinal and radial growth, as well as lack of compact cortical bone development. Indices of bone formation were reduced in ClC-7 deficient mice; however, calcein labeling indicated that mineralization occurred on most trabecular bone surfaces. Osteoid deposition had great regional variance, but an osteopetrorickets phenotype, as observed in oc/oc mice, was not apparent in the ClC-7 deficient mice. A striking finding was the presence of very large abnormal osteoclasts, which filled the bone marrow space within the ClC-7 deficient bones. The development of these giant osteoclasts could be due to altered cell fate of the ClC-7 deficient osteoclasts, caused by increased cellular fusion and/or prolonged osteoclast survival.
In summary, malfunctional ClC-7 deficient osteoclasts led to a severe developmental bone phenotype including abnormally large and non-functional osteoclasts. Bone formation paremeters were reduced; however, bone formation and mineralization were found to be heterogenous and continuing.
Muscle size in the lower limb is commonly assessed in neuromuscular research as it correlates with muscle function and some approaches have been assessed for their ability to provide valid estimates ...of muscle volume. Work to date has not examined the ability of different measurement approaches (such as cross-sectional area (CSA) measures on magnetic resonance (MR) imaging) to accurately track changes in muscle volume as a result of an intervention, such as exercise, injury or disuse. Here we assess whether (a) the percentage change in muscle CSA in 17 lower-limb muscles during 56 days bed-rest, as assessed by five different algorithms, lies within 0.5% of the muscle volume change and (b) the variability of the outcome measure is comparable to that of muscle volume. We find that an approach selecting the MR image with the highest muscle CSA and then a series of CSA measures, the number of which depended upon the muscle considered, immediately distal and proximal, provided an acceptable estimate of the muscle volume change. In the vastii, peroneal, sartorius and anterior tibial muscle groups, accurate results can be attained by increasing the spacing between CSA measures, thus reducing the total number of MR images and hence the measurement time. In the two heads of biceps femoris, semimembranosus and gracilis, it is not possible to reduce the number of CSA measures and the entire muscle volume must be evaluated. Using these approaches one can reduce the number of CSA measures required to estimate changes in muscle volume by ~60%. These findings help to attain more efficient means to track muscle volume changes in interventional studies.
Some, but not all, studies have found that low endogenous estradiol levels in postmenopausal women are predictive of fractures. The aim of this study was to examine the roles of endogenous estradiol ...(E
2
), sex hormone binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS) in the prediction of incident vertebral and nonvertebral fractures. The study subjects were 797 postmenopausal women from the population-based OPUS (Osteoporosis and Ultrasound Study) study. Spine radiographs and dual-energy X-ray absorptiometry scans were obtained for all subjects at baseline and 6-year follow-up. Nonfasting blood samples were taken at baseline for E
2
, SHBG, DHEAS, and bone turnover markers. Incident nonvertebral fractures were self-reported and verified; vertebral fractures were diagnosed at a single center from spinal radiographs. Medical and lifestyle data were obtained by questionnaire at each visit. Thirty-nine subjects had an incident vertebral fracture and 119 a nonvertebral fracture. Estradiol in the lowest quartile predicted vertebral fracture independent of confounders including age, body mass index, bone mineral density, bone turnover, fracture history, and use of antiresorptive therapy, with an OR of 2.97 (95 % confidence interval CI 1.52–5.82) by logistic regression. A calculated free estradiol index was not a stronger predictor than total E
2
. Higher SHBG predicted vertebral fracture independently of age and body mass index, but not independently of E
2
, bone mineral density, or prevalent fracture. Low DHEAS did not predict vertebral fracture. Nonvertebral fractures were not predicted by any of E
2
, SHBG, or DHEAS, either in univariate or multivariate analyses. These findings suggest that there may be mechanistic differences in the protective effect of E
2
at vertebral compared with nonvertebral sites.
Abstract Mutations in the 2Cl− /1H+ -exchanger ClC-7 impair osteoclast function and cause different types of osteoclast-rich osteopetrosis. However, it is unknown to what extent ClC-7 function has to ...be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clcn7−/− mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro . Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7−/− mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7 -related osteopetrosis.
Establishing the long-term repeatability of quantitative measures of lumbar intervertebral disc and spinal morphology is important for planning interventional studies. We aimed to examine this issue ...and to determine to what extent a smaller number of measurements per disc or vertebral level could be used to save operator time without compromising measurement precision. Twenty-one healthy male subjects were scanned at baseline and 1.5 years later. On sagittal MR-scans intervertebral disc cross-sectional area, anterior disc height, posterior disc height, intervertebral angle and intervertebral length were measured. The repeatability of the average value from all sagittal images or from 1, 3, 5 or 7 images centred at the spinous process was evaluated. Bland-Altman analysis showed all measurements to be repeatable between testing days. Intervertebral length was the most precise measurement (coefficients of variation CVs between 1.2% and 1.5%), followed by disc cross-sectional area (CVs between 2.9% and 3.6%). Variance component analysis showed that using 7 images, but not 1, 3 or 5 images, resulted in a similar level of measurement error as when measurements from all images were included.
Summary
Loss of bone mineral density occurs after discontinuation of teriparatide, if no subsequent treatment is given. Sequential raloxifene prevented rapid bone loss at lumbar spine and further ...increased bone mineral density (BMD) at femoral neck, whether raloxifene was started immediately or after a one-year delay following teriparatide treatment.
Introduction
We compared the sequential effects of raloxifene treatment with a placebo on teriparatide-induced increases in bone mineral density (BMD). A year of open-label raloxifene extended the study to assess the response with and without delay after discontinuation of teriparatide.
Methods
Following a year of open-label teriparatide 20 μg/day treatment, postmenopausal women with osteoporosis were randomly assigned to raloxifene 60 mg/day (n = 157) or a placebo (n = 172) for year 2, followed by a year of open-label raloxifene. BMD was measured by dual energy x-ray absorptiometry.
Results
The raloxifene and placebo groups showed a decrease in lumbar spine (LS) BMD in year 2 for raloxifene and placebo groups (−1.0 ± 0.3%, P = 0.004; and −4.0 ± 0.3%, P < 0.001, respectively); the decrease was less with raloxifene (P < 0.001). Open-label raloxifene treatment reversed the LS BMD decrease with a placebo, resulting in similar decreases 2 years after randomization (−2.6 ± 0.4% (raloxifene-raloxifene) and −2.7 ± 0.4% (placebo-placebo). At study end, LS and femoral neck (FN) BMD were higher than pre-teriparatide levels, with no significant differences between the raloxifene-raloxifene and placebo-raloxifene groups, respectively (LS: 6.1 ± 0.5% vs. 5.1 ± 0.5%; FN: 3.4 ± 0.6% vs. 3.0 ± 0.5%).
Conclusion
Sequential raloxifene prevented rapid bone loss at the LS and increased FN BMD whether raloxifene was started immediately or after a one-year delay following teriparatide treatment.
PDF
