Showing papers in "Journal of Bone and Mineral Research in 2009"

Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee

Abstract: RACTITIONERS OF BONE HISTOMORPHOMETRY communicate P with each other in a variety of arcane languages, which in general are unintelligible to those outside the field. Many in the bone and mineral scientific community would like to keep abreast of the contributions of histology to their subject, but are dismayed by the semantic barriers they must overcome. The need for standardization has been recognized for many years,(') during which there has been much talk but no action. To meet the needs of ASBMR members, Dr. B.L. Riggs (President, 19851986) asked the senior author to convene a committee of the Society to develop a unified system of termnology, suitable for adoption by the Journal of Bone and Mineral Research as part of its Instructions to Authors. The committee includes members from Europe and Canada as well as the U.S., and represents most existing systems of nomenclature. A circular letter seeking suggestions and information on current usage was sent to several hundred persons, with names drawn from the Society membership roster and lists of attendees at various recent conferences, to which approximately 40 replies were obtained. These confirmed the magnitude of the semantic problem (for some measurements as many as nine different terms were in use) and suggested a range of solutions likely to be generally acceptable. In formulating the new system. the committee kept in mind certain agreed general principles. First, the primary reason for change was to help other scientists understand bone histomorphometry, not to help bone histomorphometrists undcntand each other. Second. names should be self-explanatory and dcscriptive, without implicit assumptions. Third. symbols should consist mainly of abbreviations that included the first letter of each word in the same order as in the name. without subscripts or superscripts. Fourth. each symbol component should have one and only one meaning, and so eliminate ambiguity. Fifth, primary measurements should be clearly distinguished from derived indices. Finally, the chosen system should be sufficiently flexible to apply to all surfaces and all types of bone, and to accommodate any new primary measurement or derived index. The recommended system shares common elements with. but also differs substantially from. all those in current usc. was tested in practice for several months before the final forniat was chosen, and is as complex and conceptually difficult ;I\\ the field with which it deals. For those within the field we hope that increased readership of their papers will be adequate conipensation for the inconvcnicncc of learning a new systcm. For those outside the field, mastering the new system will be hard work, but if we are able to secure its acceptance by all journals with an interest in bone and mineral metabolism, the effort will only have to be expended once rather than. as at present. rcpeated many times. To this end we give the reasons for our decisions in the areas of controversy and, as well as definitions, provide methods for calculation of derived indices and

The diagnosis of osteoporosis

Abstract: VER THE YEARS many definitions of osteoporosis have been 0 offered to describe variously the outcome events (fragility fractures), the process giving rise to porous bones, or the resultant diminution of bone mass. More consistency has been achieved in recent years by the development of definitions that cover the spectrum of its manifestations. from the reduced amount of bone present to some of the consequences of bone loss. A consensus development conference statement defined osteoporosis as "a disease characterized by low bonc mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk."'" The definition has survived the rigors of the most recent consensus development confcrence."' There are, however, a number of problems which need to be addressed in adapting a conceptual definition for clinical use. Some of these problems were recently discussed by an expert panel of the World Health Organization."' This paper summarizes these issues and proposes diagnostic criteria for osteoporosis for practical use.

Vertebral fracture assessment using a semiquantitative technique

Abstract: The assessment of vertebral fracture by conventional radiography has been refined and improved using either semiquantitative or quantitative criteria. The inter- and intraobserver variability was determined for a semiquantitative visual approach that we routinely use in clinical studies for assessing prevalent and incident vertebral fractures. In addition, the semiquantitative approach was compared with a quantitative morphometric approach. The incidence and prevalence of vertebral fractures were determined in 57 postmenopausal women (age 65-75 years) by three independent observers. The radiographic basis for fracture definitions and the source of interobserver agreement for the semiquantitative technique. We conclude that the semiquantitative approach can be applied reliably in vertebral fracture assessment when performed using well-defined criteria.

Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989.

Abstract: Vertebral fractures are the classic hallmark of osteoporosis, yet little is known of their epidemiology. The incidence of clinically diagnosed vertebral fractures was therefore directly assessed in the predominantly white (European descent) population of Rochester, Minnesota. Altogether, 341 Rochester residents were radiologically diagnosed for the first time with one or more vertebral fractures in the 5 year study period, 1985-1989. The overall age- and sex-adjusted incidence rate was 117 per 100,000 person-years (95% CI, 105 to 130). The age-adjusted rate in women (145 per 100,000 person-years) was almost twice that in men (73 per 100,000 person-years). Of all fractures, 47 (14%) followed severe trauma, 282 (83%) followed moderate or no trauma, and 12 (3%) were pathologic. Incidence rates for fractures following moderate trauma were higher in women than in men and rose steeply with age in both genders. In contrast, fractures following severe trauma were more frequent in men, and their incidence increased less with age. These Rochester rates are greater than those previously reported from studies in Britain and Sweden but lower than the incidence rates extrapolated from a prevalence study in this population.

Perspective : how many women have osteoporosis ?

Abstract: Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined. Noninvasive bone mineral measurements can be used to define a state of heightened fracture risk (osteopenia), or the ultimate clinical manifestation of fracture can be assessed (established osteoporosis). If bone mineral measurements more than 2 standard deviations below the mean of young normal women represent osteopenia, then 45% of white women aged 50 years and over have the condition at one or more sites in the hip, spine, or forearm on the basis of population-based data from Rochester, Minnesota. A smaller proportion is affected at each specific skeletal site: 32% have bone mineral values this low in the lumbar spine, 29% in either of two regions in the proximal femur, and 26% in the midradius. Although this overall estimate is substantial, some other serious chronic diseases are almost as common. More importantly, low bone mass is associated with adverse health outcomes, especially fractures. The lifetime risk of any fracture of the hip, spine, or distal forearm is almost 40% in white women and 13% in white men from age 50 years onward. If the enormous costs associated with these fractures are to be reduced, increased attention must be given to the design and implementation of control programs directed at this major health problem.

The direct examination of three‐dimensional bone architecture in vitro by computed tomography

Abstract: We describe a new method for the direct examination of three-dimensional bone structure in vitro based on high-resolution computed tomography (CT). Unlike clinical CT, a three-dimensional reconstruction array is created directly, rather than a series of two-dimensional slices. All structural indices commonly determined from two-dimensional histologic sections can be obtained nondestructively from a large number of slices in each of three orthogonal directions. This permits a comprehensive description of structural variation within a specimen and greatly facilitates the study of structural anisotropy. A measure of three-dimensional connectivity (Euler number/tissue volume) has been determined for the first time in human cancellous bone and shown to correlate with several two-dimensional histomorphometric indices. The method has the potential for overcoming many of the limitations of current approaches to the study of bone architecture at the microscopic level.

New approaches for interpreting projected bone densitometry data

Abstract: Bone densitometry using dual-photon absorptiometry (DPA) or dual-energy x-ray absorptiometry (DXA) has become a standard method for assessing bone mineral content in the spine and other skeletal regions. A projected areal density, referred to as bone mineral density (BMD,g/cm2), is normally calculated to assess regional bone density and strength. We demonstrate that this measure can be misleading when used to compare bones of different sizes due to inherent biases caused by bone thickness differences. For example, assuming that volumetric bone density remains constant and bony linear dimensions are proportional to height, a 20% increase in height would result in a 20% increase in both the thickness and the BMD of any bone. We describe new analysis methods to reduce the confounding effect of bone size, and we introduce a parameter, bone mineral apparent density (BMAD, g/cm3), that better reflects bone apparent density. Using this parameter, we calculate a quantity that serves as an index of bone strength (IBS, g2/cm4) for whole vertebral bodies. These analyses were applied to lumbar spine (L2-4) DXA measurements in a population of women 17-40 years old and appear to offer advantages to conventional techniques.

Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo

Abstract: Bisphosphonates inhibit bone resorption and are therapeutically effective in diseases of increased bone turnover, such as Paget's disease and hypercalcemia of malignancy. The mechanisms by which they act remain unclear. Proposed mechanisms include inhibition of osteoclast formation from precursors and inhibitory or toxic effect on mature osteoclasts. We have developed a new in vitro model to study osteoclast survival and in this paper present in vitro and in vivo evidence that may explain both the observed reduction in osteoclast numbers and in bone resorption by mature osteoclasts, namely that bisphosphonates induce programmed cell death (apoptosis). Three bisphosphonates (risedronate, pamidronate, and clodronate) caused a 4- to 24-fold increase in the proportion of osteoclasts showing the characteristic morphology of apoptosis in vitro. This observation was confirmed in vivo in normal mice, in mice with increased bone resorption, and in nude mice with osteolytic cancer metastases, with similar-fold increases to those observed in vitro. Of the three compounds, risedronate, the most potent inhibitor of bone resorption in vivo, was the strongest inducer of osteoclast apoptosis in vitro. Osteoclast apoptosis may therefore be a major mechanism whereby bisphosphonates reduce osteoclast numbers and activity, and induction of apoptosis could be a therapeutic goal for new antiosteoclast drugs.

Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study.

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.

Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis

Abstract: Changes of bone turnover with aging are responsible for bone loss and play a major role in osteoporosis Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation and their potential role in determining bone mass in the elderly have not been investigated To address this issue, we have measured a battery of new sensitive and specific markers of bone turnover in a population-based study of 653 healthy women analyzed cross-sectionally, including 432 women postmenopausal from 1 to 40 years, and the data were correlated with bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at different skeletal sites Bone formation was assessed by serum osteocalcin (OC), serum bone-specific alkaline phosphatase (B-ALP), serum C-propeptide of type I collagen (PICP), and bone resorption by the urinary excretion of two pyridinoline cross-linked peptides (NTX and CTX) Bone turnover increased in perimenopausal women with both irregular menses and elevated serum follicle stimulating hormone (FSH) Menopause induced a 37-52% and 79-97% increase in the bone formation and bone resorption marker levels, respectively (p < 00001 except for PICP) In postmenopausal women, bone formation markers did not decrease with age When resorption markers were corrected by whole body bone mineral content (BMC), the fraction of bone resorbed per day was not correlated with age in postmenopausal women and remained elevated for up to 40 years after menopause In premenopausal women, the bone turnover rate accounted for only 0-10% of the variation in whole body BMC, total hip, distal radius, and lumbar spine BMD With increasing time after menopause, the importance of the bone turnover rate as a determinant of bone mass increased at all sites and accounted for up to 52% of the BMD variance in elderly women Thus, in women 20 years or more postmenopause, bone turnover was higher in those in the lowest quartile than in those in the highest quartile of BMD In elderly women, 20 years since menopause and over, but not in younger ones, serum PTH was negatively correlated with serum 25-hydroxyvitamin D (r = -022, p < 005) and explained only 5-8% of the bone turnover variance (p < 001-0001) These data indicate that the overall rates of both bone formation and bone resorption remain high in elderly women The rate of bone turnover appears to play an increasing role as a determinant of bone mass with increasing time since menopause with a high bone turnover rate being associated with a low bone mass Thus assessing bone marker levels may be useful in the evaluation of osteoporosis risk In elderly women, secondary hyperparathyroidism caused in part by reduced serum 25-hydroxyvitamin D appears to be a marginal determinant of an increased bone turnover rate

Effects of weight and body mass index on bone mineral density in men and women : the Framingham study

Abstract: We evaluated the association of weight and bone mass in elderly male and female subjects of the Framingham osteoporosis study, a subset of the Framingham study cohort. By examining the differences in the correlations of weight with bone mass among men and women in weight-bearing and non-weight-bearing sites and weight change since early adulthood, we attempted to understand different ways in which weight or body mass index affects bone mass. During biennial examination 20 of the Framingham cohort (1988–1989), 693 women and 439 men (mean age 76 years) had proximal femur bone mineral density assessed by dual-photon absorptiometry (DPA) and radius bone mass assessed by single-photon absorptiometry. The majority of these subjects also had spine measurements by DPA. Subjects had been weighed repeatedly over 40 years. After adjusting for other factors affecting bone density, we found that both recent weight and body mass index explained a substantial proportion of the variance in bone mineral density for all sites in women (8.9–19.8% of total variance, all p < 0.01) and for only weight-bearing sites (femur and spine) in men (2.8–6.9% of total variance, all p < 0.01). For bone mineral density at the proximal radius, weight and body mass index accounted for < 1% of variance in men (p NS). Weight change since biennial examination 1 (1948–1951) was the strongest explanatory factor for bone mineral density among women at all sites, but weight change did not affect radius bone mineral density in men. The effect of weight and of weight change on bone mineral density was in general much less in men than in women. Our results suggest that the strong effect of weight on bone mineral density is due to load on weight-bearing bones in both sexes. The sex difference is unexplained but may be due to adipose tissue production of estrogen in women after menopause.

Distinct proliferative and differentiated stages of murine MC3T3‐E1 cells in culture: An in vitro model of osteoblast development

Abstract: We examine clonal murine calvarial MC3T3-E1 cells to determine if they exhibit a developmental sequence similar to osteoblasts in bone tissue, namely, proliferation of undifferentiated osteoblast precursors followed by postmitotic expression of differentiated osteoblast phenotype. During the initial phase of developmental (days 1-9 of culture), MC3T3-E1 cells actively replicate, as evidenced by the high rates of DNA synthesis and progressive increase in cell number, but maintain a fusiform appearance, fail to express alkaline phosphatase, and do not accumulate mineralized extracellular collagenous matrix, consistent with immature osteoblasts. By day 9 the cultures display cuboidal morphology, attain confluence, and undergo growth arrest. Downregulation of replication is associated with expression of osteoblast functions, including production of alkaline phosphatase, processing of procollagens to collagens, and incremental deposition of a collagenous extracellular matrix. Mineralization of extracellular matrix, which begins approximately 16 days after culture, marks the final phase of osteoblast phenotypic development. Expression of alkaline phosphatase and mineralization is time but not density dependent. Type I collagen synthesis and collagen accumulation are uncoupled in the developing osteoblast. Although collagen synthesis and message expression peaks at day 3 in immature cells, extracellular matrix accumulation is minimal. Instead, matrix accumulates maximally after 7 days of culture as collagen biosynthesis is diminishing. Thus, extracellular matrix formation is a function of mature osteoblasts. Ascorbate and beta-glycerol phosphate are both essential for the expression of osteoblast phenotype as assessed by alkaline phosphatase and mineralization of extracellular matrix. Ascorbate does not stimulate type I collagen gene expression in MC3T3-E1 cells, but it is absolutely required for deposition of collagen in the extracellular matrix. Ascorbate also induces alkaline phosphatase activity in mature cells but not in immature cells. beta-glycerol phosphate displays synergistic actions with ascorbate to further stimulate collagen accumulation and alkaline phosphatase activity in postmitotic, differentiated osteoblast-like cells. Mineralization of mature cultures requires the presence of beta-glycerol phosphate. Thus, MC3T3-E1 cells display a time-dependent and sequential expression of osteoblast characteristics analogous to in vivo bone formation. The developmental sequence associated with MC3T3-E1 differentiation should provide a useful model to study the signals that mediate the switch between proliferation and differentiation in bone cells, as well as provide a renewable culture system to examine the molecular mechanism of osteoblast maturation and the formation of bone-like extracellular matrix.

The prevalence of vertebral deformity in european men and women: the european vertebral osteoporosis study

Abstract: Our aim was to determine the prevalence of radiographically defined vertebral deformity, as a marker of vertebral osteoporosis, in different regions and populations within Europe. We used a cross-sectional population-based survey. Population-based sampling frames were obtained from 36 centers in 19 European countries. Stratified random sampling was used to recruit 15,570 males and females aged 50-79 years. Lateral spinal radiographs were taken according to a standardized protocol, and all X-rays were evaluated centrally. Vertebral deformity was morphometrically defined according to the published methods of McCloskey and Eastell. Based on the McCloskey method, the mean center prevalence of all deformities was 12% in females (range 6-21%) and 12% in males (range 8-20%). The prevalence increased with age in both sexes though the gradient was steeper in females. There was substantial geographical variation, with the highest rates in Scandinavian countries. Radiographically defined vertebral deformity is a common disorder and equally frequent in males and females. Using standardized methodology, there is important variation in occurrence across Europe, which might suggest clues to pathogenesis.

Long-term fracture prediction by bone mineral assessed at different skeletal sites

Abstract: Bone mineral density (BMD) was measured at the lumbar spine and cervical and intertrochanteric regions of the proximal femur by dual-photon absorptiometry and bone mineral content was assessed at the distal and midradius by single-photon absorptiometry in an age-stratified random sample of 304 Rochester, Minnesota women aged 30-94 years. Over follow-up extending to 10 years (median 8.3 years), 93 women experienced 163 new fractures. After adjusting for age, these bone mineral measurements predicted the likelihood of any incident fracture due to moderate trauma, with relative hazards varying from 1.4 to 1.6 per SD decrease in baseline bone mineral. A 1 SD decrease in lumbar spine BMD increased the risk of a new vertebral fracture comparably to a 17 year increase in age; a 1 SD decrease in femoral BMD was comparable to a 13-14 year increase in age on the risk of a hip fracture. We conclude that bone mineral measurements made at a variety of skeletal sites can predict the occurrence for at least 8-10 years of moderate trauma fractures of the sort that might be related to osteoporosis.

Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.

Abstract: The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.

Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis

Abstract: In summary, available data demonstrate that IL-1 and TNF are the causative agents underlying the bone loss induced by estrogen deficiency. Indeed, these factors are produced in bone and the bone marrow, released in larger amounts from cells of estrogen-deficient subjects, and indispensable for reproducing the effects of estrogen deficiency in bone. These observations support the hypothesis that the bone sparing effect of estrogen is due to the ability of the hormone to block osteoclastogenesis, the activation of mature osteoclasts and, as recently demonstrated, the rate of apoptotic osteoclast death. Although IL-1 and TNF play a prominent causal role in these events, the bone-sparing effect of estrogen is mediated by numerous cytokines which, by simultaneously stimulating multiple target cells, induce effects that are not accounted for by any one single factor (Fig. 2). The ability of estrogen to regulate some, but not all, the cytokines involved in this process is not inconsistent with this hypothesis because cytokines have potent synergistic effects. Thus, a considerable increase in bone resorption may result from a relatively small increase in the concentration of only a few of the bone-resorbing factors present in the bone microenvironment. This concept is best illustrated by the study of Miyaura et al. demonstrating that the concentrations of either IL-1, IL-6, IL-6 receptor, or prostaglandins detected in the bone marrow of OVX mice are insufficient to account for the increased bone resorption caused by estrogen withdrawal. In contrast, the increase in bone resorption induced by OVX can be explained by the cumulative effects of these cytokines. Thus, a better understanding of the cooperative effects of cytokines and a recognition that the contribution of individual cytokines to postmenopausal bone loss varies with the passage of time after menopause are necessary to fully understand the mechanism of action of estrogen in bone. Although the relevance of individual bone-targeting cytokines in species specific, the development of transgenic mice with activatable or deactivatable promoters is likely to result in a further clarification of the integrated action of estrogen-regulated cytokines in human bone cells and lay the foundations for the use of cytokine inhibitors in the treatment of postmenopausal osteoporosis.

Bone mineral loss and recovery after 17 weeks of bed rest

Abstract: The purpose of this work was to determine the rate and extent of bone loss and recovery from long-term disuse and in particular from disuse after exposure to weightlessness. For this purpose, bed rest is used to simulate the reduced stress and strain on the skeleton. This study reports on the bone loss and recovery after 17 weeks of continuous bed rest and 6 months of reambulation in six normal male volunteers. Bone regions measured were the lumbar spine, hip, tibia, forearm, calcaneus, total body, and segmental regions from the total-body scan. The total body, lumbar spine, femoral neck, trochanter, tibia, and calcaneus demonstrated significant loss, p less than 0.05. Expressed as the percentage change from baseline, these were 1.4, 3.9, 3.6, 4.6, 2.2, and 10.4, respectively. Although several areas showed positive slopes during reambulation, only the calcaneus was significant (p less than 0.05), with nearly 100% recovery. Segmental analysis of the total-body scans showed significant loss (p less than 0.05) in the lumbar spine, total spine, pelvis, trunk, and legs. During reambulation, the majority of the regions demonstrated positive slopes, although only the pelvis and trunk were significant (p less than 0.05). Potential redistribution of bone mineral was observed: during bed rest the bone mineral increased in the skull of all subjects. The change in total BMD and calcium from calcium balance were significantly (p less than 0.05) correlated, R = 0.88.

Simple measurement of femoral geometry predicts hip fracture: The study of osteoporotic fractures

Abstract: Based on engineering principles, geometric measurements of femoral size should be related to femoral strength and the risk for hip fracture. To evaluate whether a simple measurement of femoral geometry is associated with hip fracture risk, we obtained dual x-ray absorptiometry scans of the proximal femur on 8074 white women age 67 or older. During an average of 1.6 years of follow-up, 64 participants suffered hip fractures. In all fracture cases and in a random sample of 134 women who did not subsequently suffer a hip fracture, we measured hip axis length (the distance from greater trochanter to inner pelvic brim), neck width, and the neck/shaft angle on the scan printout, with the observer blinded to subsequent fracture status of the participant. Results were analyzed using multiple logistic models, and odds ratios were determined. After adjustment for age, each standard deviation decrease in femoral neck bone mineral density increased hip fracture risk 2.7-fold (95% confidence interval 1.7, 4.3), and each standard deviation increase in hip axis length nearly doubled the risk of hip fracture (odds ratio = 1.8; 95% CI 1.3, 2.5). The relationship between hip axis length and fracture risk persisted even after adjustment for age, femoral neck density, height, and weight. A longer hip axis length was associated with an increased risk of both femoral neck (OR = 1.9; 95% CI 1.3, 3.0) and trochanteric fractures (1.6; 1.0, 2.4). We found no significant association between the neck width (1.1; 0.8, 1.5) or the neck/shaft angle (1.4; 0.9, 2.2) and risk of hip fracture.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates.

Abstract: We estimated genetic effects on bone density in pre- and postmenopausal twins and critically considered the assumptions of the twin model. Bone mass in the radius, lumbar spine, and hip, anthropometric measurements, usual calcium and caffeine intake, tobacco and alcohol use, number of pregnancies and live births, menstrual history, usual physical activity, and medical history were measured in a volunteer sample of 171 twin pairs [124 monozygotic (MZ) and 47 dizygotic (DZ)], aged 25-80, free of diseases known to affect bone mass or mineral metabolism. At all skeletal sites, MZ intraclass correlations exceeded DZ correlations for both pre- and postmenopausal women, yielding highly significant estimates of heritability for bone mass. Adjustments for height, age, and environmental characteristics did not reduce the heritability estimates. However, many of these estimates were unrealistically high, suggesting some violation(s) of the assumptions of the twin model. Thus, the familial resemblance in bone mass is due primarily to genetic effects at all skeletal sites and at all ages, although the importance of genetic effects is diminished with aging, as evidenced by increasing within-MZ pair variability in older women. Because of failures in the assumptions of the twin model, however, particularly the greater MZ environmental similarity and the probability of gene interaction, heritability estimates are probably too high and require cautious interpretation.

Classification of vertebral fractures

Abstract: Although it is a cardinal feature of involutional osteoporosis, there is often disagreement on what constitutes a vertebral fracture. We measured vertebrae T4-L5 in 52 healthy women to develop a normal range (mean +/- 3 SD) for vertebral shape and used these data to assess the prevalence of vertebral fractures. We classified vertebral fractures by type of deformity (wedge, biconcavity, or compression) and further by the degree of deformity (grades 1 and 2). In 195 postmenopausal women who were an age-stratified random sample of the Rochester population (ages 47-94), 40 (21%) had vertebral fractures (mean, 2 per person). There was a similar number of compression and wedge fractures, and grade 2 fractures were as common as grade 1. In a referral sample of 74 women with suspected osteoporosis, 62 (84%) had vertebral fractures (mean, 3.3 per person). Wedge fractures were most common, and grade 2 fractures were more common than grade 1. The distribution of type and grade of fractures differed between the two patient groups (P less than 0.01). Bone mineral density of the lumbar spine was related to mean fracture grade (r = -0.33, P less than 0.05) and to fracture number (r = -0.57, P less than 0.001) but not to fracture type. We conclude that a comprehensive approach is required in describing vertebral fractures. Using this approach we found distortion in the fracture characteristics of women referred to an osteoporosis clinic compared to women in the community.

Skeletal disease in primary hyperparathyroidism.

Abstract: Most patients with primary hyperparathyroidism in the 1980s do not have evidence of bone disease when they are evaluated by conventional radiography. We sought to determine whether skeletal involvement can be appreciated when more sensitive techniques, such as bone densitometry and bone biopsy, are utilized. We investigated 52 patients with primary hyperparathyroidism. They had mild hypercalcemia, 2.8 +/- 0.03 mmol/liter (11.1 +/- 0.1 mg/dl), low normal phosphorus, 0.9 +/- 0.03 mmol/liter (2.8 +/- 0.1 mg/dl), and no symptoms or specific radiological signs of skeletal involvement. The greatest reduction in bone mineral density was found at the site of predominantly cortical bone, the radius (0.54 +/- 0.1 g/cm; 79 +/- 2% of expected), whereas the site of predominantly cancellous bone, the lumbar spine (1.07 +/- 0.03 g/cm2), was normal (95 +/- 3% of expected). The site of mixed composition, the femoral neck (0.78 +/- 0.14 g/cm2), gave an intermediate value (89 +/- 2% of expected). Preferential involvement of cortical bone with apparent preservation of cancellous bone in primary hyperparathyroidism was confirmed by percutaneous bone biopsy. Over 80% of patients had a mean cortical width below the expected mean, whereas cancellous bone volume in over 80% of patients was above the expected mean. The results indicate that the majority of patients with asymptomatic primary hyperparathyroidism have evidence by bone densitometry and bone biopsy for cortical bone disease. The results also indicate that the mild hyperparathyroid state may be protective of cancellous bone. The therapeutic implications of these observations await further longitudinal experience with this study population.

Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis

Abstract: The assessment of radiographs for vertebral fractures is important in the clinical evaluation of patients with suspected osteoporosis, in the epidemiological evaluation of elderly populations, and in clinical trials of osteotrophic drugs. The purpose of this study is to compare visual semiquantitative (SQ) approaches and quantitative morphometric approaches for assessing prevalent and incident vertebral fractures in postmenopausal osteoporosis. We analyzed lateral thoracolumbar spine radiographs (baseline and approximately 3.5 year follow-up) of 503 women (age > or = 65) randomly selected from the Study of Osteoporotic Fractures (SOF) population. SQ assessment by an experienced radiologist graded vertebral fractures from 0 (normal) to 3 (severe). Incident fractures by SQ were defined as an increase of > or = 1 grade on follow-up radiographs. Trained research assistants visually triaged women as normal, uncertain, or probably fractured and visually flagged vertebrae with moderate/severe (grade > or = 2) prevalent fractures or with any (grade > or = 1 change) incident fracture. The radiographs were also digitized by research assistants, and quantitative morphometry (QM) was used to classify vertebral deformities at several cut-offs based on standard deviation (SD) reductions in height ratios from normal means, e.g., QM > or = 3 SD. Incident fractures by QM were defined as a decrease in height of more than 15% (QM15) on follow-up radiographs. Finally, a combination of these methods was used to detect moderate/severe prevalent fractures and any grade of incident fractures. In the overall analysis, the prevalence of fractures varied from 14 to 33% and the incidence from 5 to 10% by woman, depending upon the method and cut-off criteria. In the detailed analysis, considering visually triaged uncertain as abnormal, triage by research assistants detected 97.0% (163/168) of women with SQ grade > or = 1 fractures and 100% (70/70) with SQ grade > or = 2 fractures. Visual flagging by research assistants detected 88.5% (108/122) of SQ > or = 2 prevalent fractures (kappa score, kappa = 0.82) and 85.2% (52/61) of SQ incident fractures (kappa = 0.79). QM > or = 3 SD detected 37.9% (141/372) of SQ > or = 1 prevalent fractures (kappa = 0.51) and 79.5% (97/122) of SQ > or = 2 prevalent fractures (kappa = 0.68), plus 18 vertebrae without SQ fractures. QM 15 detected 59% (36/61) of SQ incident fractures (kappa = 0.70), plus five vertebrae without SQ incident fractures. The combination assessment detected 92% (112/122) of SQ > or = 2 prevalent fractures (kappa = 0.76) and 84% (51/61) of SQ incident fractures (kappa = 0.91). The precision errors of QM vertebral height measurements (baseline versus follow-up) ranged from 2.71 to 2.92%. Nevertheless, excluding the 5719 vertebrae that were clearly normal by morphometry, i.e., within 2 SD of the normal means at both baseline and follow-up, two-thirds (358/556) of the remaining vertebrae changed classification by at least 1 SD category. Visual triage and visual flagging by research assistants appear to be highly effective methods for vertebral fracture assessment in osteoporosis, potentially reducing the number of false-positive and false-negative fractures detected by QM, at least relative to SQ by the radiologists. There is higher concordance among the visual approaches studied than between the visual SQ and quantitative morphometric approaches, with QM having limited ability to detect mild fractures but good ability to detect moderate/severe fractures, as classified by SQ. Use of a combination of sensitive qualitative and quantitative criteria, with adjudication by an experienced radiologist, is feasible and draws upon the relative strengths of each of the methods. Quantitative morphometry should not be performed in isolation, particularly when applying highly sensitive morphometric criteria at low threshold levels, without visual assessment to confirm the detected prevalent or incident vertebral defor

Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling

Abstract: Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/beta-catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/beta-catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost(-/-) mice were resistant to mechanical unloading-induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/beta-catenin signaling was not altered by unloading in Sost(-/-) mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/beta-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis.

Universal standardization for dual X‐ray absorptiometry: Patient and phantom cross‐calibration results

Abstract: The comparison of patient data among different dual x-ray absorptiometry (DXA) scanners is complicated because no universally accepted cross-calibration procedure or standard currently exists. This study was performed under the auspices of the International DXA Standardization Committee to establish appropriate cross-calibration parameters. Posteroanterior (PA) lumbar spine measurements of 100 women, ages 20-80 years (mean 52.6 +/- 16, range of BMD = 0.4-1.6 g/cm2) were obtained on a Norland XR26 Mark II, a Lunar DPX-L, and a Hologic QDR 2000 densitometer using standard procedures (pencil beam mode for all three scanners). Area, BMC, and BMD results from the different scanners were compared for all patients. In addition, the European spine phantom (ESP) and the European spine phantom prototype (ESP prototype), as well as standard phantoms from all three manufacturers, were evaluated on the three systems. To achieve universal scanner calibration, we used the intercept and slope of the patient's correlations and the value of the middle vertebra of the ESP as a reference point in a series of standardization formulas, and we have expressed the results as sBMD (mg/cm2). The correlations of the patients' spinal BMD values were excellent for each of the three scanner pairs. The average absolute difference in patient spinal BMD values (L2-4) between Hologic and Norland was 0.012 g/cm2 (1.3%); it was 0.113 g/cm2 (11.7%) between Hologic and Lunar and 0.118 g/cm2 (12.2%) between Norland and Lunar. The phantoms' regression lines approximated those of the patient regression lines, and the phantoms with only one measurement point were very close to the patients' regression lines. After applying the standardization formulas, the average absolute differences for the 100 patients were 28 mg/cm2 (2.7%) for Hologic/Norland, 23 mg/cm2 (2.2%) for Hologic/Lunar, and 29 mg/cm2 (2.8%) for Norland/Lunar. Average BMD results for the patients before correction were 0.972 mg/cm2 for Hologic, 1.100 g/cm2 for Lunar, and 0.969 g/cm2 for Norland. After correction, sBMD results for patients were 1045 mg/cm2 for Hologic, 1047 mg/cm2 for Lunar, and 1043 mg/cm2 for Norland. The standardization approach as performed in our study provided compatibility of DXA results obtained on different scanners.

Risk factors for hip fracture in European women: the MEDOS Study. Mediterranean Osteoporosis Study.

Abstract: The aims of this study were to determine common international risk factors for hip fracture in women aged 50 years or more. We studied women aged 50 years or more who sustained a hip fracture in 14 centers from Portugal, Spain, France, Italy, Greece, and Turkey over a 1-year period. Women aged 50 years or more selected from the neighborhood or population registers served as controls. Cases and controls were interviewed using a structured questionnaire on work, physical activity, exposure to sunlight, reproductive, history and gynecologic status, height, weight, mental score, and consumption of tobacco, alcohol, calcium, coffee, and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), short fertile period, low physical activity. lack of sunlight exposure, low milk consumption, no consumption of tea, and a poor mental score. No significant adverse effects of coffee or smoking were observed. Moderate intake of spirits was a protective factor in young adulthood, but otherwise no significant effect of alcohol intake was observed. For some risks, a threshold effect was observed. A low BMI and milk consumption were significant risks only in the lowest 50% and 10% of the population, respectively. A late menarche, poor mental score, low BMI and physical activity, low exposure to sunlight, and a low consumption of calcium and tea remained independent risk factors after multivariate analysis, accounting for 70% of hip fractures. Excluding mental score and age at menarche (not potentially reversible), the attributable risk was 56%. Thus, about half of the hip fractures could be explained on the basis of the potentially reversible risk factors sought. In contrast, the use of risk factors to "predict" hip fractures had moderate sensitivity and specificity. We conclude that variations in lifestyle factors are associated with significant differences in the risk of hip fracture, account for a large component of the total risk, and may be of some value in selecting individuals at high risk.

Association of bone mineral density with polymorphism of the estrogen receptor gene

Abstract: PvuII and XbaI restriction fragment length polymorphisms (RFLPs) of the estrogen receptor (ER) gene and its relation to bone mineral density (BMD) were examined in 238 postmenopausal healthy women aged 45-91 years (66.3 +/- 0.6 years, mean +/- standard error of the mean [SEM]) in Japan. The RFLPs were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of and small letters the presence of restriction sites. In the PPxx genotype (n = 18), Z score values of BMD were significantly lower than those for other genotypes (n = 220) (lumbar spine, -0.746 vs. -0.065 [p = 0.022]; total body, -0.482 vs. 0.308 [p = 0.002]). We classified the subjects into three genotypes with allelic haplotype: homozygote of the Px haplotype was expressed as the 11 genotype, heterozygote of the Px haplotype as the 10 genotype, and the one lacking the Px haplotype as the 00 genotype. The PpXx genotype was not included in this analysis because the allelic haplotypes are uncertain. The Px haplotype was associated with a low BMD in postmenopausal women (Z score for the lumbar spine, -0.746 vs. -0.279 vs. 0.083, for the 11, 10, 00 genotypes, respectively [p = 0.029]; Z score for the total body, -0.482 vs. 0.164 vs. 0.427, respectively [p = 0.003]). We suggest that some variation of the ER gene linked to these RFLPs is associated with low BMD and that this at least partly explains the cause of postmenopausal osteoporosis in Japanese women.

Heritable and life-style determinants of bone mineral density

Abstract: Familial resemblance in bone mineral density at five skeletal sites was measured among 160 adult members of 40 families. Each family included a postmenopausal mother, one premenopausal daughter, one son, and the children's father. Similarities in selected life-style factors thought to influence bone density, such as physical activity, smoking, alcohol use, and diet, were also evaluated. Bone density was measured by dual-energy (total body, femoral neck, and lumbar spine) or single-photon (radius and os calcis) absorptiometry. Correlation coefficients between the midparent Z score and offspring Z scores of bone mineral density ranged from 0.22 to 0.52 among daughters and from 0.27 to 0.58 among sons. Adjustment of bone density for age, height, weight, and significant life-style or environmental factors yielded heritability estimates for the five skeletal sites between 0.46 and 0.62. That is, 46-62% of variance in bone density was attributable to heredity. Most estimates derived from the group of daughters were similar to those from the sons. These observations provide support for a significant contribution of heredity to bone density. However, an individual's life-style may account for a potentially large proportion of the nonheritable variance in bone density.

Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation

Abstract: Chronic immune responses and inflammatory reactions in rheumatoid arthritis (RA) often cause severe destruction of cartilage and bone, but its mechanism is still a matter of controversy. We reported that interleukin-6 (IL-6) alone does not induce osteoclast formation, but soluble interleukin-6 receptors (sIL-6R) triggered the formation in the presence of IL-6 in cocultures of murine osteoblastic cells and bone marrow cells. In this study, we examined the involvement of sIL-6R and IL-6 in joint destruction in patients with RA. Although the frequency of patients having osteoclast-like multinucleated cells in synovium derived from the knee joint was not significantly different between RA (65%) and osteoarthritis (OA) patients (43%), the number of osteoclast-like cells found in the synovium was greater in the former than in the latter. Multinucleated cells obtained from RA synovium expressed the osteoclast-specific phenotype such as tartrate-resistant acid phosphatase, carbonic anhydrase II, vacuolar proton-ATPase and vitronectin receptors at similar levels to those from a human giant cell tumor of bone. The concentration of both IL-6 and sIL-6R was significantly higher in the synovial fluids from patients with RA than with OA. The concentration of IL-6 and sIL-6R correlated well with the roentgenologic grades of joint destruction. Dose-response curves for human IL-6 and human sIL-6R in inducing osteoclast-like cell formation in cocultures indicated that the RA synovial fluids contained sufficient IL-6 and sIL-6R to induce osteoclastogenesis. When synovial fluids from RA and OA patients were added to the cocultures, some of the RA synovial fluids containing high levels of IL-6 and sIL-6R stimulated osteoclast-like cell formation, which was strikingly inhibited by adding anti-IL-6R antibody simultaneously. These results suggest that IL-6 in the RA synovial fluids is at least in part responsible for joint destruction in the presence of sIL-6R through osteoclastogenesis.