Showing papers in "Osteoporosis International in 1995"

Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques

Abstract: Assessment of precision errors in bone mineral densitometry is important for characterization of a technique's ability to detect logitudinal skeletal changes Short-term and long-term precision errors should be calculated as root-mean-square (RMS) averages of standard deviations of repeated measurements (SD) and standard errors of the estimate of changes in bone density with time (SEE), respectively Inadequate adjustment for degrees of freedom and use of arithmetic means instead of RMS averages may cause underestimation of true imprecision by up to 41% and 25% (for duplicate measurements), respectively Calculation of confidence intervals of precision errors based on the number of repeated measurements and the number of subjects assessed serves to characterize limitations of precision error assessments Provided that precision error are comparable across subjects, examinations with a total of 27 degrees of freedom result in an upper 90% confidence limit of +30% of the mean precision error, a level considered sufficient for characterizing technique imprecision We recommend three (or four) repeated measurements per individual in a subject group of at least 14 individuals to characterize short-term (or long-term) precision of a technique

Proximal femur bone mineral levels of US adults

Abstract: This paper describes bone mineral levels in the proximal femur of US adults based on a nationally representative sample of 7116 men and women aged 20 years and older. The data were collected in phase 1 of the third National Health and Nutrition Examination Survey (NHANES III, 1988-1991) using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in five selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter, Ward's triangle and total. These variables are provided separately by age and sex for non-HIspanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA). BMD and BMC in the five ROI tended to decline with age, whereas area did not. BMD and BMC were highest in NHB, intermediate in MA and lowest in NHW, but areas were highest in NHW, intermediate in NHB and lowest in MA. Men had greater BMD, BMC and area than women in all three race/ethnic groups. Differences by age, sex or race/ethnicity tended to be the largest in Ward's triangle, followed by the femur neck; patterns in the trochanter, intertrochanter and total ROI were reasonably similar to each other. This report provides extensive data on femur bone mineral levels of adults from one of the largest samples available to date and should be valuable as reference data for other studies which examine this skeletal site in adults.

Stress distributions within the proximal femur during gait and falls: Implications for osteoporotic fracture

Abstract: The rates of fracture at sites with different relative amounts of cortical and trabecular bone (hip, spine, distal radius) have been used to make inferences about the pathomechanics of bone loss and the existence of type I and type II osteoporosis. However, fracture risk is directly related to the ratio of tissue stress to tissue strength, which in turn is dependent not only on tissue composition but also tissue geometry and the direction and magnitude of loading. These three elements determine how the load is distributed within the tissue. As a result, assumptions on the relative structural importance of cortical and trabecular bone, and how these tissues are affected by bone loss, can be inaccurate if based on regional tissue composition and bone density alone. To investigate the structural significance of cortical and trabecular bone in the proximal femur, and how it is affected by bone loss, we determined the stress distributions in a normal and osteoporotic femur resulting from loadings representing: (1) gait; and (2) a fall to the side with impact onto the greater trochanter. A three-dimensional finite element model was generated based on a representative femur selected from a large database of femoral geometries. Stresses were analyzed throughout the femoral neck and intertrochanteric regions. We found that the percentage of total load supported by cortical and trabecular bone was approximately constant for all load cases but differed depending on location. Cortical bone carried 30% of the load at the subcapital region, 50% at the mid-neck, 96% at the base of the neck and 80% at the intertrochanteric region. These values differ from the widely held assumption that cortical bone carries 75% of the load in the femoral neck and 50% of the load at the intertrochanteric region. During gait, the principal stresses were concentrated within the primary compressive system of trabeculae and in the cortical bone of the intertrochanteric region. In contrast, during a fall, the trabecular stresses were concentrated within the primary tensile system of trabeculae with a peak magnitude 4.3 times that present during gait. While the distribution of stress for the osteoporotic femur was similar to the normal, the magnitude of peak stress was increased by between 33% and 45%. These data call into question several assumptions which serve as the basis for theories on the pathomechanics of osteoporosis. In addition, we expect that the insight provided by this analysis will result in the improved development and interpretation of non-invasive techniques for the quantification of in vivo hip fracture risk.

Direct clinical and welfare costs of osteoporotic fractures in elderly men and women.

Abstract: Osteoporosis is an increasing health care problem in all aging populations, but overall direct costs associated with the total fracture burden of osteoporosis remain uncertain. We have examined direct costs associated with 151 osteoporotic fractures occurring between 1989 and 1992 in a large cohort of elderly men and women followed prospectively as part of the Dubbo Osteoporosis Epidemiology Study. The median cost of hospital treated fractures was $A10,511 per fracture and for fractures treated on an outpatient basis $A455 in 1992 Australian dollars. Femoral neck fractures were the most expensive fractures ($15,984 median cost). There was no significant difference in costs between men and women for either hospital- or outpatient-treated fractures. Rehabilitation hospital costs comprised the largest proportion of costs (49%) for hospital-treated fractures. Community services comprised the major cost (40%) of outpatient-treated fractures. Univariate predictors of costs were quadriceps strength and bone density, although multivariate analysis showed quadriceps strength to be the best overall predictor of costs. The predicted annual treatment costs in Australia for atraumatic fractures occurring in subjects > or = 60 years was $A779 million or approximately $A44 million per million of population per annum. Estimated total osteoporotic fracture-related costs for the Australian population were much higher than previously reported. The majority of direct costs (95%) were incurred by hospitalized patients and related to hospital and rehabilitation costs. Extrapolation of these data suggests that the direct costs for hip fracture alone will increase approximately twofold in most Western countries by 2025. Improving the cost-effectiveness of treating osteoporotic fractures should involve reduced hospitalization and/or greater efficiency in community rehabilitation services. The costs of various approaches to osteoporosis prevention must be placed into the context of these direct costs and prevention should target men as well as women.

Calcaneal ultrasonic measurements discriminate hip fracture independently of bone mass

Abstract: We studied 336 elderly white women, of whom 22 had previously suffered a hip fracture and 22 had previously suffered a vertebral fracture. All subjects were 60 years old or older with a mean age of 73.7 years. Measurements of ultrasonic transmission velocity (UTV), broad-band ultrasonic attenuation (BUA) and stiffness (STF) were made at the os calcis using a Lunar Achilles ultrasound device. Measurements of lumbar spine bone mineral density (L2–4 BMD) and femoral neck BMD were made using dual-energy X-ray absorptiometry. The fracture groups were significantly older and had more years since menopause than the control groups. Logistic regression showed that measurements of UTV, STF and BUA discriminated between fracture and non-fracture subjects for both the hip (p<0.001) and spine (p<0.05). Femoral neck BMD discriminated both hip and vertebral fractures from controls (p<0.001 andp<0.01, respectively). Spinal BMD discriminated between subjects with vertebral fractures and those without (p<0.01), but not hip fractures (p=0.64). For hip fracture, areas under receiver-operating characteristic (ROC) curves were 0.85 for UTV, 0.83 for STF, 0.79 for BUA, 0.78 for femoral neck BMD and 0.53 for spinal BMD. For vertebral fracture, areas under the ROC curve were 0.68 for UTV, 0.70 for STF, 0.66 for BUA, 0.66 for femoral neck BMD and 0.67 for spinal BMD. To determine whether calcaneal ultrasonic measurements discriminated, independently of BMD, fracture from control groups, UTV, BUA and STF were adjusted for BMD, age and years since menopause using multiple regression analysis and the residuals from the regressions were incorporated into a logistic regression analysis. Adjusted ultrasonic measurements discriminated hip fracture from control groups (p<0.005 for UTV;p<0.05 for BUA;p<0.01 for STF) but not vertebral fracture (p=0.37 for UTV;p=0.53 for BUA;p=0.25 for STF). These results show that, when ultrasonic measurements were adjusted for BMD and age, they still discriminated between hip fracture and control groups. This finding supports the hypothesis that ultrasonic measurements contain information about bone strength not contained in bone density measurements that may be useful in predicting hip fractures. Therefore, calcaneal ultrasound measurements may provide a safe, low-cost addition to bone densitometry.

Better discrimination of hip fracture using bone density, geometry and architecture

Abstract: Bone density predicts the risk of hip fracture. Because hip strength is determined by bone geometry and architecture as well as density, we tested which variables in geometry and architecture were independent discriminators of hip fracture and, if combined with density, improved the discrimination of fracture from non-fracture over bone density alone. The design was a case-control study. The subjects were Caucasian women over the age of 60 years who had sustained a hip fracture after the age of 58 years (n=22), and controls matched for age and weight (n=43) and unmatched controls (n=317) with no history of hip fracture. Variables in density, geometry and architecture were obtained from dual-energy X-ray absorptiometry images and from radiographs of the upper end of the femur. In a univariate model, of the measures of bone mass, the best discriminator of hip fracture was bone mineral density of the neck of femur; of the geometric measurements, it was hip axis length; and of the measurements of bone architecture, it was Singh grade. In a multivariate model, these three variables were shown to be independent discriminators of hip facture. When hip axis length was combined with bone mineral density, there was significant improvement in discrimination of hip fracture (p=0.014), and when Singh grade was combined with hip axis length and bone mineral density there was a further significant improvement (p=0.002). In logistic regression models using hip axis length and Singh grade adjusted for femoral neck bone mineral density, age and weight, the area under the receiver-operating characteristics (ROC) curve for femoral neck density, hip axis length and Singh grade together was significantly greater than for femoral neck density alone (p=0.006). Models that combine bone mass (density), geometry (hip axis length) and architecture (Singh grade) significantly improve the discrimination of hip fracture over bone density by itself. If these models can be shown to be equally useful in predicting hip fracture prospectively and can be obtained from dual-energy X-ray absorptiometry, their use will increase the ability to identify subjects at most risk of hip fracture.

Spinal bone mineral assessment in postmenopausal women: A comparison between dual X-ray absorptiometry and quantitative computed tomography

Abstract: We compared quantitative computed tomography (QCT) and dual X-ray absorptiometry (DXA) with respect to their ability to discriminate subjects with and without prevalent vertebral fractures. In 240 post-menopausal women (mean age 63.7±6.9 years) lateral spine radiographs (T4-L4) were reviewed for the presence of vertebral fracture. Using a semiquantitative technique to grade the severity of vertebral deformities, we classified fractures as mild, moderate or severe (grade 1 to 3, respectively). Postero-anterior DXA (PA-DXA) and lateral DXA (L-DXA) measurements (L2–4) as well as QCT measurements of the lumbar spine (T12-L3 or L1–14) were obtained in all women. Seventy-two women were diagnosed with at least one fracture, and of these 40 were graded as mild. Comparing normal women with fractured women, we found the area under the receiver operating characteristics (ROC) curves to be greatest for QCT (0.81), followed by L-DXA (0.72) and PA-DXA (0.65). The differences among all three techniques were significant. Comparing the normal women with women having only mild fractures, the areas under the ROC curves were 0.79, 0.73 and 0.63 for QCT, L-DXA and PA-DXA, respectively. Significant differences existed between QCT and PA-DXA as well as between L-DXA and PA-DXA. Logistic regression analysis also revealed the highest age-adjusted odds ratios for QCT (3.67; 2.25–5.97) while L-DXA and PA-DXA showed substantially lower odds ratios (2.00; 1.39–2.87, and 1.54; 1.11–2.15, respectively). We conclude that low bone density as measured by QCT, PA-DXA or L-DXA is significantly associated with the prevalence of vertebral fractures. Of the methods studied, QCT of trabecular bone offered the best discriminatory capability. L-DXA proved to be superior to PA-DXA in its diagnostic sensitivity, particularly in women with mild fracture. Mild vertebral fractures are associated with decreased spinal bone density and may be regarded as osteoporotic deformities.

Fracture protection provided by long-term estrogen treatment

Abstract: The objective of the study was to determine the incidence rate of osteoporotic fractures among elderly women who had long-term postmenopausal estrogen replacement therapy (ERT) and to compare this with the incidence rate in women who had not used estrogen. In a previous retrospective cohort study based on medical record review in 1982, we showed that long-term ERT was associated with lower incidence of wrist and vertebral fractures. We have extended our follow-up of 490 women by adding a mean 8 years to the observation period, which more than triples the number of osteoporotic fractures. At the Kaiser Permanente Medical Center, San Francisco, a large health maintenance organization, a review of computer pharmacy records from 1968 through 1971 identified 245 postmenopausal women; all had begun estrogen within 3 years of menopause and had used estrogen for at least 5 years. From the same pharmacy records, 245 age-matched postmenopausal non-users were identified. Among estrogen users, mean length of use was 17.0 years, mean follow-up after treatment was 7.3 years and mean dose of conjugated oral estrogen was 0.9 mg daily. We found statistically significant reduction in the incidence of wrist and vertebral fractures in users compared with non-users. The age-adjusted incidence ratios (95% confidence intervals for wrist fractures were 0.55 (0.32–0.92) and for vertebral fractures were 0.57 (0.41 –0.80). These results were not statistically significantly altered after adjustment for age of menopause, body mass index and smoking. It is concluded that long-term ERT confers statistically significant protection against wrist and vertebral fractures.

Bone loss in patients with inflammatory bowel disease: A prospective study

Abstract: To assess the rate of bone loss in patients with inflammatory bowel disease, we prospectively studied 35 patients (17 women) aged 36±13 (range 17–60) years, 14 of whom had Crohn's disease and 21 with ulcerative colitis (including 12 with ileoanal anastomosis). Bone mineral density was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck. The follow-up was 19±8 months. During this period, 14 patients received oral steroids. Lumbar bone density changes expressed as a percentage per year were −3.1±4.9%, −6.4±7.5% and +2.0±4.0% in Crohn's disease and ulcerative colitis without and with ileoanal anastomosis respectively (p=0.007). The same pattern was observed at the femoral neck. Mean annual lumbar bone density changes were −6.2±7.0% and +0.9±3.9% in patients with and without steroids during follow-up (p=0.002). We conclude that patients with inflammatory bowel disease are at risk of lumbar and femoral bone loss. However, bone loss is not observed in patients with ileoanal anastomosis.

Comparison of semiquantitative and quantitative techniques for the assessment of prevalent and incident vertebral fractures

Abstract: To compare visual semiquantitative (SQ) reading and quantitative morphometry (QM) for assessing prevalent and incident vertebral fractures, radiographs of the thoracolumbar spine were evaluated in 400 (only baseline films) and 335 (baseline and follow-up films) postmenopausal women with osteopenia as defined by aT-score of less than 2 SD below young normals. QM was performed using different cutoff thresholds, and the SQ reading was performed by three radiologists independently. A joint consensus reading of the radiographs by all participating radiologists was used as a reference standard. Our results indicate that the concordance within SQ methods is excellent, and it is higher than that between SQ and QM regardless of the cutoff criteria used. This finding was consistent for the diagnosis of prevalent as well as incident vertebral fractures. For prevalent fractures the use of the 2.5 SD cutoff criterion provided the highest concordance with the consensus reading and with the radiologists' reading, thereby providing high sensitivity (70.23%) with moderate specificity (98.76%) relative to the consensus reading when compared with the 3 SD or 4 SD cutoff criteria. For the diagnosis of incident vertebral fractures the best agreement between our consensus reading and QM was found for an absolute reduction of 6 mm and for a combination of relative and absolute reduction of 15% and 3 mm in vertebral height. The respective sensitivities and specificities for the two criteria were 51%/99.9% and 75.4%/98.9%, respectively. Even though the consensus reading may favor the reader's evaluation over QM, the assessment of prevalent and incident fractures using QM alone may not be sufficiently reliable for detection of vertebral fractures in epidemiological studies and clinical trials. It should be performed principally in conjunction with a trained radiologist or a highly experienced clinician.

Age-related hip fractures in men: clinical spectrum and short-term outcomes.

Abstract: Clinical spectrum, treatment and short-term outcomes were assessed among the 131 Rochester, Minnesota, men who contracted an initial hip fracture due to moderate trauma during 1978-89. Three-fourths of falls leading to hip fracture occurred indoors with little seasonality, and 91% of fractures were in men 65 years of age or older. The ratio of cervical to intertrochanteric femur fractures was 1.4:1, and there was a tendency toward more neurological conditions among the patients with cervical fractures. Hemiarthroplasty and total hip replacement were mostly performed for cervical fractures, while internal fixation was preferred for intertrochanteric fractures. In-hospital mortality was 11.5%, and the 30-day case fatality rate was 16.0%. Age and postoperative deterioration of mental status significantly increased the risk of early death, the latter even after adjustment in a multivariate model, while comorbidity had a suggestive but not statistically significant influence on mortality. More than half the men were discharged to nursing homes, and 79% of the patients who survived at 1 year resided in nursing homes or intermediate care facilities or were attended by home care. Only 41% of survivors recovered their prefracture level of functioning and nearly 60% of patients limped and required a cane or walker. After implementation of the prospective payment system in 1984, the length of hospital stay was reduced, but there was no change in early mortality rates, in the duration of physical therapy following fracture or in attendance at nursing homes. The results of this population-based study demonstrate the strong impact of hip fractures on short-term outcomes in men.

European semi-anthropomorphic spine phantom for the calibration of bone densitometers: assessment of precision, stability and accuracy. The European Quantitation of Osteoporosis Study Group.

Abstract: Up to now it has not been possible to reliably cross-calibrate dual-energy X-ray absorptiometry (DXA) densitometry equipment made by different manufacturers so that a measurement made on an individual subject can be expressed in the units used with a different type of machine. Manufacturers have adopted various procedures for edge detection and calibration, producing various normal ranges which are specific to each individual manufacturer's brand of machine. In this study we have used the recently described European Spine Phantom (ESP, prototype version), which contains three semi-anthropomorphic “vertebrae” of different densities made of simulated cortical and trabecular bone, to calibrate a range of DXA densitometers and quantitative computed tomography (QCT) equipment used in the measurement of trabecular bone density of the lumbar vertebrae. Three brands of QCT equipment and three brands of DXA equipment were assessed. Repeat measurements were made to assess machine stability. With the large majority of machines which proved stable, mean values were obtained for the measured low, medium and high density vertebrae respectively. In the case of the QCT equipment these means were for the trabecular bone density, and in the case of the DXA equipment for vertebral body bone density in the posteroanterior projection. All DXA machines overestimated the projected area of the vertebral bodies by incorporating variable amounts of transverse process. In general, the QCT equipment gave measured values which were close to the specified values for trabecular density, but there were substantial differences from the specified values in the results provided by the three DXA brands. For the QCT and Norland DXA machines (posteroanterior view), the relationships between specified densities and observed densities were found to be linear, whereas for the other DXA equipment (posteroanterior view), slightly curvilinear, exponential fits were found to be necessary to fit the plots of observed versus specified densities. From these plots, individual calibration equations were derived for each machine studied. For optimal cross-calibration, it was found to be necessary to use an individual calibration equation for each machine. This study has shown that it is possible to cross-calibrate DXA as well as QCT equipment for the measurement of axial bone density. This will be of considerable benefit for large-scale epidemiological studies as well as for multi-site clinical studies depending on bone densitometry.

Quality control of DXA instruments in multicenter trials.

Abstract: Dual-energy X-ray absorptiometry (DXA) has become the measurement of choice for multicenter trials with bone density endpoints. When performing DXA measurements with several different systems, it is important to implement a quality assurance program to guarantee that any observed density changes are real and not due to machine and/or operator variability. In this study, we present a series of procedures based on phantom measurements designed to monitor DXA instrument stability. Techniques for longitudinal evaluation of machine performance and cross-calibration of instruments are described. These procedures are then demonstrated using quality assurance data collected from a number of different DXA scanners. Together these methods provide a defined approach to instrument quality control. Though based primarily on the use of spinal phantoms, these procedures can be generalized for use in any multicenter DXA study.

Specific evaluation of localized bone mass and bone loss in the rat using dual-energy X-ray absorptiometry subregional analysis.

Abstract: Dual-energy X-ray absorptiometry (DXA), together with the use of ultra-high resolution software, recently appeared as an accurate method for determining bone mineral density (BMD) in the rat. In order to assess the ability of this technique to detect changes in bone mass in the rat rapidly and precisely, we measured BMD at various sites of the femur using DXA subregional analysis. In particular, we studied the BMD of the metaphyseal part of the femur (M-BMD) rich in trabecular bone, and compared the values obtained with the cancellous bone volume measured by histomorphometry. In short-term ovariectomized animals (experiment 1), M-BMD was the only parameter to differentiate statistically between 10 ovariectomized (OVX) and 10 SHAM-operated (SHAM) rats (−11.2%,p<0.01) 9 days after surgery. M-BMD still expressed the greatest variation between OVX and SHAM rats 42 days following ovariectomy (experiment 2) (−16.1%,p<0.001 v −6.2%,p<0.01 for the total femur BMD) and confirmed previous data demonstrating a greater loss of cancellous than cortical bone after cessation of ovarian activity. M-BMD was highly correlated with cancellous bone volume (BV) in normal (r=0.82,p<0.001,n=30), OVX (r=0.77,p<0.001,n=22) and SHAM (r=0.88,p<0.001,n=21) rats. Furthermore, subcutaneous treatment with rat parathyroid hormone fragment (1–34) (r-PTH(1-34)) partially and significantly protected animals from trabecular osteopenia induced by OVX; there was a similar degree of protection of BV and M-BMD (50% and 61% respectively), while BMD of the entire femur achieved complete protection. This M-BMD measurement, specifically reflecting cancellous bone mass as confirmed by the correlation study and the response to PTH treatment, is a sensitve and simple method which can be used to assess any precocious modifications of bone density under physiopathological or therapeutic conditions in experimental rat models of bone loss.

Risk factors for hip fracture in a high incidence area: a case-control study from Oslo, Norway.

Abstract: The aim of this population-based matched case-control study was to evaluate the effect of risk factors for hip fracture in Oslo, Norway, which has some of the highest incidence rates ever reported. The study population comprised all non-institutionalized persons 50 years or older living in the catchment area of two Oslo hospitals, and cases were 246 patients admitted for hip fracture during a 1-year period. The controls were randomly selected from the study population, matched 1:1 for age and sex. Hip fracture was associated with lean body stature, smoking, low grip strength and decreased levels of physical activity, and inversely with length of education. In addition, hip fracture was inversely related to indicators of total food intake (number of meals per day, frequency of dinners, and slices of bread per day). A relation between hip fracture and low vitamin D intake was also suggested, whereas no association with dietary calcium intake was found. Finally, increased risk of fracture was seen in persons reporting two or more hospital admissions in the previous 2 years, and in those reporting weight reduction due to poor appetite during the previous year. In conclusion, the risk factor pattern for hip fracture was much the same in the elderly population of Oslo as previously described in other populations with a lower incidence of fracture. This study also indicates a relation between hip fracture and low food intake.

Caffeine and the calcium economy revisited

Abstract: We report an analysis of data from 560 calcium balance studies carried out on 190 women aged 34.8–69.3 years at the time of study. The main purposes were to confirm a previously observed association between caffeine intake and calcium balance, and to attribute the association, if possible, to specific component(s) of balance. We found a caffeine relationship such that for every 6 fl oz (177.5 ml) serving of caffeine-containing coffee, calcium balance was more negative by 0.114 mmol/day (4.6 mg/day) (P<0.001). The relationship was localized to the input side of the balance equation, and both of its components (i.e. calcium intake and calcium absorption efficiency) were independently and inversely associated with caffeine intake. There was no evidence that the putative caffeine effect is confined to, or is greater among, subjects with low calcium intakes or those who are older or estrogen-deprived. The magnitude of the negative effect of caffeine on calcium balance suggests that it can be offset by increasing calcium intake by about 1 mmol (40 mg) for every 177.5 ml serving of caffeine-containing coffee.

A review of the recent advances in magnetic resonance imaging in the assessment of osteoporosis

Abstract: Osteoporosis is a common metabolic disorder with considerable associated morbidity and mortality. The loss of bone mineral integrity and the resultant occurrence of atraumatic fractures are typically symptomatic of the disease. Currently skeletal status is commonly assessed using non-invasive conventional radiography and scintigraphy as well as densitometric techniques such as quantitative computed tomography and dual-energy X-ray absorptiometry. But, apart from gross bone mineral density, the fine structure of trabecular bone also plays an important role in defining the biomechanical competence of the skeleton. Recently attention has been focused on deriving measures that provide information about not only trabecular bone density but also microstructure. Magnetic resonance imaging (MRI) is one such new technique which potentially may provide information pertaining to bone density and structure as well as to occult fracture detection. Cortical bone produces a signal void in MR images, due to the fact that it contains very few mobile protons that give rise to a signal in MRI; also the MR relaxation time T2 of these protons is very short which produces a very fast decay of the MR signal during image acquisition. However, the trabecular bone network affects the MR properties of bone marrow. The difference in the magnetic properties of trabecular bone and bone marrow generates local imperfections in the magnetic field. The MR signal from bone marrow is modified due to these imperfections and the MR relaxation time T2* of marrow is shortened. The extent of relaxation time shortening and hence loss of signal intensity is proportional to the density of trabecular bone and marrow interfaces and their spatial architecture. Recent investigation in this area include studies aimed at quantifying marrow relaxation times and establishing their relationship to trabecular bone density and structure. In addition, with advances in imaging software and hardware, MR images at in-plane resolutions of 78–200 µm may be obtained. The trabecular bone structure is clearly revealed in such images and studies aimed at the development of high-resolution MRI techniques combined with quantitative image analysis techniques are currently under way. These potentially useful techniques for assessing osteoporosis and predicting fracture risk are reviewed in this paper.

Cost-effectiveness of fracture prevention in established osteoporosis.

Abstract: This study presents the results of a computer simulation model for calculating the cost-effectiveness and cost-utility of treating patients with established osteoporosis in order to reduce the risk of fractures. The results are based on Swedish data for risk of fracture and costs. The treatment intervention modelled is based on treatment of a 62-year-old woman with established osteoporosis. The cost per hip fracture avoided is 350,000 SEK, assuming a 50% reduction in the risk of fracture due to 5 years of treatment. A sensitivity analysis for changes in the cost and effectiveness of treatment, the risk of fracture and the discount rate is performed. The cost per life-year gained and the cost per quality-adjusted life-year (QALY) gained is presented to enable comparison of the cost-effectiveness of treating osteoporosis with that of other health care interventions. A comparison between treating the same woman for osteoporosis and mild hypertension shows a cost per life-year gained of 220,000 SEK and 128,000 SEK respectively. Cost per QALY gained is very similar for the two interventions: 105,000 SEK and 103,000 SEK respectively. This model provides a tool to enable clinicians, administrators and health policy makers to analyze and understand the economic aspects of a major health policy issue.

Diagnostic value of ultrasound analysis and bone densitometry as predictors of vertebral deformity in postmenopausal women.

Abstract: Bone fractures depend not only on bone density, but also on bone quality. Ultrasound (US) has been proposed as a technique for evaluating skeletal status. Speed of sound (SOS) and broadband ultrasound attenuation (BUA) are the US properties currently used to assess bone strength and fragility. In 304 postmenopausal women (age 58.8±5.5 years) we measured: bone mineral density (BMD) of the lumbar spine (by dual-energy X-ray absorptiometry), SOS, BUA and Stiffness in the os calcis (using an Achilles machine). In all subjects we performed lateral lumbar and thoracic radiographs. Morphometric parameters were derived by measuring the anterior, middle and posterior height of each vertebral body, to obtain a semiquantitative grading of vertebral fractures as follows: 0, no vertebral deformity; 1, any vertebral height reduced between 20% and 25%; 2, any vertebral height reduced between 25% and 40%; 3, any vertebral height reduced more than 40%. On the basis of the number and severity of vertebral deformities the women were divided into: group 1 (n=79), normal; group 2(n=80), mild; group 3 (n=85), moderate; and group 4 (n=60), severe. Mean values of SOS, BUA, Stiffness and BMD were significantly lower (p<0.001) in women with vertebral deformity than in normals. In the whole population SOS, BUA and Stiffness values were significantly correlated with BMD. SOS, BUA and Stiffness values were significantly decreased (p<0.001) with vertebral deformity, as was BMD. Receiver operating characteristic (ROC) curve analysis showed BMD to be slightly better than Stiffness in discriminating among groups. Logistic regression analysis showed that BMD, BUA, SOS and Stiffness were independent predictors of vertebral fracture risk. Ultrasound parameters were still significant independent predictors of vertebral fracture even after adjusting for BMD.

Biochemical markers of bone turnover to monitor the bone response to postmenopausal hormone replacement therapy.

Abstract: Hormone replacement therapy (HRT) prevents postmenopausal bone loss, and is therefore increasingly prescribed to prevent the development of postmenopausal osteoporosis. Because of individual differences in the response to HRT as well as problems with compliance, it has been debated how the skeletal response to HRT should be monitored. When estrogen production decreases at the menopause, a number of biochemical markers of bone turnover increase considerably in the order of 50%–100% from baseline. When HRT is instituted, the markers decrease again within the following 3–6 months. In the present prospective study we investigated whether the determination of biochemical markers of bone turnover may be useful for monitoring the skeletal effect of HRT. Seventy-six early postmenopausal women received HRT and 43 received placebo. The treatment period was 24 months and the women were followed with repeated bone mass measurements (every 3 months) which allowed calculation of the bone loss. Serum and urine samples were collected at 3, 6, 12 and 24 months. The placebo group lost a significant amount of bone mineral density in both the forearm and the spine (p<0.001), whereas the HRT group did not. There was, however, a relatively large overlap of values between the HRT and placebo groups, especially in the spine. After 3 months' treatment the correlation between the changes in the markers and the bone loss wasr=0.59, and this value increased tor=0.66 at 6 months andr=0.76 andr=0.77 at 12 and 24 months, respectively. The present study thus indicates that biochemical markers of bone turnover may be of value for monitoring the bone response to HRT.

Rationale for the use of alendronate in osteoporosis.

Abstract: Bisphosphonates are being used in disorders associated with accelerated resorption of bone, particularly Paget's disease of bone and the bone disease of malignancy. Their undoubted biological efficacy and relatively low apparent toxicity make them attractive candidates for the management of osteoporosis. The bisphosphonate alendronate has many characteristics which suggest that it is suitable for use in osteoporosis. It is a potent inhibitor of osteoclast-mediated bone resorption with no adverse effect on the mineralization of bone. Earlier studies have shown it to be one of the most active bisphosphonates in Paget's disease and the hypercalcemia of malignancy. In common with other bisphosphonates tested thus far, alendronate appears to inhibit bone loss in a variety of experimental models of osteoporosis. Long-term studies are needed to determine its steady-state effects on bone mass in man. Most data indicate that alendronate is capable at least of decreasing the rate of bone loss, and might even induce increments in bone mass for many years. Since the experimental studies show that the increase in bone mass observed with alendronate is associated with an increase in bone strength, its use is likely to decrease the frequency of fractures. However, direct clinical evidence for this requires the outcome of well-designed long-term prospective studies.

Differences in the Characteristics of Responders and Non-Responders in a Prevalence Survey of Vertebral Osteoporosis

Abstract: Men and women aged 50 years and over were recruited for participation in a population-based prevalence survey of vertebral osteoporosis from 36 centres in 19 European countries. All subjects were invited to attend by letter of invitation for a “lifestyle” interview and lateral spinal radiograph. The aim of this analysis was to investigate how far those who agreed to attend were representative of the target population and thus whether any important level of non-response bias existed. To address this a second invitation was sent to all non-responders and, in 20 centres, a sample of ultimate non-responders was contacted by mail, telephone or home visit and given a shortened version of the lifestyle questionnaire. Compared with the sample of non-responders, responders might be considered less at risk from osteoporosis in that as a group they took more exercise and were less likely to be current smokers. Other factors suggested the contrary in that they consumed less calcium and were more likely to have suffered a previous fracture. Amongst responders, these factors appeared also to be related to the timing of response. Thus compared with delayed responders, those who participated after a first letter of invitation took more exercise, were less likely to be smokers and more likely to have suffered a previous fracture. However, in contrast to the results suggested by the non-response survey early responders consumed more calcium than late responders. The magnitude of the differences between responders and non-responders was small (less than 10% for most of the categorical variables) and the differences were not consistently in the direction of an increased or decreased risk of osteoporosis. Additionally the size or direction of these differences was not consistently influenced by the response rate based on classifying centres into those with a high, medium or low response rate. This suggests that in this multicentre study response bias probably does not have a major influence on the prevalence estimates of vertebral fracture. In epidemiological studies of osteoporosis comparison of the lifestyle differences between early and late responders provides useful information concerning response characteristics.

Cortical thickness assessed by peripheral quantitative computed tomography: Accuracy evaluated on radius specimens

Abstract: The purpose of the present study was to evaluate the accuracy of peripheral quantitative computed tomography (pQCT) in measuring the thickness of the radial cortex. Thirty left forearm specimens were scanned on an XCT 960 Stratec pQCT device using a 2.5 mm thick slice at the junction of the middle and the distal third of the radius. Cortical and trabecular areas were assessed using a threshold procedure; cortical thickness was subsequently calculated assuming a circular ring model for the radius. Cortical thickness was also measured on the true shape of bone using an iterative contour detection procedure. Subsequently 2.5 mm thick resin-embedded cylindrical radial specimens, matched with the site of pQCT examination, were obtained and contact radiographs were performed. After tenfold magnification, the cortical and trabecular areas of the specimens were measured using computerized planimetry and cortical thickness was calculated assuming a circular ring model. The cortical thickness could be assessed by pQCT in all cases using the threshold algorithm (mean (SD) 2.51 (0.58) mm) and in 21 cases could be directly measured on the true shape of bone (2.62 (0.32) mm). The cortical thickness of the specimens showed good correlation and high proportionality with that measured using pQCT with either the threshold algorithm (r=0.941, slope=0.976) or the iterative contour detection procedure (r=0.883, slope=0.987). In conclusion, pQCT is able to assess the thickness of the radial cortex, at the junction of the middle and the distal third, with high accuracy.

Histomorphometric Analysis of Iliac Crest Bone Biopsies in Placebo- Treated Versus Fluoride-Treated Subjects

Abstract: In a 4-year controlled, prospective trial, histomorphometric analysis was used to compare the tissue-level skeletal effects of fluoride therapy in 43 postmenopausal women (75 mg NaF/day) with those of 35 matching placebo subjects; all subjects received 1500 mg/day elemental calcium supplement In addition to an initial, baseline biopsy, a second biopsy was obtained after 6, 18, 30 or 48 months Measurements were made on a third biopsy obtained from 8 subjects following at least 72 months of fluoride therapy The change in cancellous bone volume or trabecular thickness in fluoride-treated subjects was not different from a change in placebo-treated subjects However, paired analysis in the fluoride-treated subjects indicated that bone volume was increased between the first and second biopsies (p < 0005) Both osteoid length and width were significantly increased in fluoride compared with placebo subjects; however, only the osteoid surface increased linearly (r = 063, p < 0001) The mineral apposition rate and relative tetracycline-covered bone surface were not different between fluoride and placebo treatment, although they were decreased in both groups in the second biopsy The tetracycline-covered bone surface returned to normal in the third biopsy Definitive evidence for osteomalacia is a prolonged mineralization lag time, which following fluoride treatment was found to be increased 9-fold in the second biopsy and 4-fold in the third biopsy Further evidence for osteomalacia was increased osteoid thickness by 6 months, evidence of focal areas of interstitial mineralization defects, and broad tetracycline labels of low fluorescence intensity In the third biopsies, osteoclastic resorption was observed beneath osteoid seams Fluoride therapy increased the cortical width compared with placebo treatment (p < 002), and increased the osteoid surface in Haversian canals, but did not change the osteoid width, resorption surface or cortical porosity After an initial rise, serum fluoride levels remained constant, and the urine values fell slightly The bone fluoride concentration rose throughout the treatment period, and was correlated with the change in osteoid-covered bone surface (r = 056, p < 0001) Although we found definitive evidence for osteomalacia, the cause of the osteomalacia was not determined in this study On the other hand, the presence of bone resorption beneath unmineralized osteoid and of osteocyte halos is suggestive of hyperparathyroidism Thus, it is possible that the strong stimulus for bone formation brought about by fluoride therapy resulted in relative calcium deficiency

Influence of anthropometric parameters on ultrasound measurements of Os calcis.

Abstract: Few data have been published concerning the influence of height, weight and body mass index (BMI) on broadband ultrasound attenuation (BUA), speed of sound (SOS) and Lunar “stiffness” index, and always in small population samples The first aim of the present cross-sectional study was to determine whether anthropometric factors have a significant influence on ultrasound measurements The second objective was to establish whether these parameters have real effect on bone or whether their infuence is due only to measurement errors We measured, in 271 healthy French women (mean age 77±11 years; range 31–97 years), the following parameters: age, height, weight, lean and fat body mass, heel width, foot length, knee height and height of the external malleolus (HEM) Simple linear regression analyses between ultrasound and anthropometric parameters were performed Age, height and heel width were significant predictors of SOS; age, height, weight, foot length, heel width, HEM, fat mass and lean mass were significant predictors of BUA; age, height, weight, heel width, HEM, fat mass and lean mass were significant predictors of stiffness In the multiple regression analysis, once the analysis had been adjusted for age, only heel width was a significant predictor for SOS (p=00007), weight for BUA (p=00001), and weight (p=00001) and heel width (p=0004) for the stiffness index Besides their statistical meaning, the regression coefficients have a more clinically relevant interpretation which is developed in the text These results confirm the influence of anthropometric factors on the ultrasonic parameter values, because BUA and SOS were in part dependent on heel width and weight The influence of the position of the transducer on the calcaneus should be taken into account to optimize the methods of measurement using ultrasound

The relationship between osteoarthritis of the hands, bone mineral density, and osteoporotic fractures in elderly women

Abstract: To study the relationship between osteoarthritis (OA) and osteoporosis (OP), radiographic osteoarthritis lesions of the hands (HOA) were quantified in 300 healthy women, aged 75 years or more, as a subgroup of a cohort originally recruited for a multi-centre study of risk factors for femoral neck fracture. The HOA combined score (i.e. the sum of the grades of joint-space narrowing, osteophytes, erosions and joint misalignment), the osteophytosis score and the joint-space narrowing score were calculated on a radiograph of both hands. Bone mineral density (BMD) was measured using dual-energy X-ray absortiometry (Lunar DPX) at the femoral neck, Ward's triangle and the total body. BMDs of the total spine, lumbar spine, and the upper and lower limbs were derived from the regional analyses of the total body measurement. Correlations between bone mass, HOA scores and other variables were explored by multiple linear regression and stepwise logistic regression analysis. The HOA combined score was positively correlated with increasing age but not with body mass index. In the multiple regression analyses the HOA combined score positively correlated with BMD at all sites, except the femoral neck and Ward's triangle; the osteophytosis score correlated with BMD at all sites; and no correlation was found between BMD and the joint-space narrowing score. According to stepwise logistic regression and after adjustment of BMD for age, women with an HOA combined score higher than 20 had signficantly higher BMD values at all skeletal sites. Sixty-nine women (23%) reported a history of osteoporotic fracture; among them, 20 (6.6%) reported a history of vertebral fracture. The OA score of both subgroups was significantly lower than that of women with no history of fracture. These data suggest that in elderly women the severity of HOA is positively correlated with bone mass and that women with a high score of HOA more rarely report a history of osteoporotic fracture.

Cortical Ultrasound Velocity as an Indicator of Bone Status

Abstract: Normative population data are reported here for velocity of ultrasound in tibial cortical bone in a population-based sample of both men and women (n=371). The cortical measurement is highly precise with reproducibility of the order of 0.5%. As with heel and patellar trabecular velocity, tibial cortical velocity declines with age from the fourth through the ninth decades. The rate is 1.7 m/s per year in men and 4.1 m/s per year in women. Tibial cortical velocity values correlate with patellar velocity and with forearm mineral, with correlation coefficients ranging from + 0.46 to +0.54 in women and +0.27 to +0.43 in men (P<0.002 for all). Tibial velocity averaged 77–104 m/s lower (2–3%: equal to about 1 SD of the young adult normal distribution) in individuals with a history of low-energy appendicular fractures (P<0.05), and the difference remained significant after adjusting for age. However, there were no perceptible differences in tibial velocity for those with and without vertebral fractures. Odds ratios derived from logistic regression showed an approximate twofold increase in likelihood of low-energy appendicular fracture for every standard deviation decrement in velocity. Comparison of tibial velocity with patellar velocity and forearm density in the same individuals revealed tibial velocity to be more strongly associated with appendicular fractures than patellar velocity for women and about the same for men, and less strongly associated than patellar velocity for vertebral fractures. We conclude that tibial cortical velocity provides useful information about bone status in populations at risk for osteoporosis, and seems particularly well suited for assessing appendicular fracture risk.

Sodium monofluorophosphate increases vertebral bone mineral density in patients with corticosteroid-induced osteoporosis

Abstract: Corticosteroid-induced osteoporosis, which particularly affects the axial skeleton and the proximal femur, is characterized by a state of low bone remodelling. Fluoride is a potent stimulator of trabecular bone formation which could potentially be useful in the treatment of corticosteroid-induced osteoporosis. We investigated the effects of sodium monofluorophosphate (26 mg/day of fluoride) combined with 1000 mg of calcium (MFP-calcium-treated group), or of calcium alone (control), given for 18 months, on bone mineral density (BMD) of lumbar spine (LS), femoral neck (FN) and midfemoral shaft (FS) in 48 patients with corticosteroid-induced osteoporosis. Mean ages were 49.4±3.1 and 51.6±3.0 years (mean± SEM), duration of corticosteroid therapy 7.5±1.8 and 9.3±1.7 years, and mean daily dose of prednisone 18.2±2.3 and 12.1±1.1 mg in the MFP-calcium-treated group and controls, respectively. Initial BMDs (expressed as theZ-score, i.e. the difference in standard deviations from age- and sex-matched normal subjects) were −1.5±0.2 and −1.2±0.2 for LS, −1.4± 0.2 and −1.3±0.2 for FN, and −0.8±0.3 and −0.6±0.3 for FS, in the MFP-calcium-treated group and controls, respectively. Analysis by linear regression of 6-monthly measurement values revealed BMD changes of +7.8 ±2.2 versus + 3.6±1.3% (p<0.02) for LS, −1.5±1.8 versus +0.9 ±1.8% for FN, and −1.1±1.1 versus −0.5±1.4% for FS after 18 months of follow-up in the MFP-calcium-treated group and controls, respectively. For comparison, 17 patients with idiopathic osteoporosis (mean age 63.9±2.0 years), with initial BMDs of −1.3±0.4, −1.6±0.3 and −0.8±0.4 (Z-score for LS, FN and FS, respectively), received MFP and calcium for 22.1±1.7 months. BMD changes in idiopathic osteoporosis were +9.3±2.7% (p<0.005), −1.3±2.0% and +0.6± 0.9% for LS, FN and FS, respectively. These results indicate that the combination sodium monofluorophosphate and calcium was more efficient than calcium alone in increasing lumbar spine BMD in patients with corticosteroid-induced osteoporosis; neither femoral neck nor femoral shaft BMD was affected. Moreover, these effects were similar in patients with corticosteroid-induced and idiopathic osteoporosis.

A randomized, double-masked, placebo-controlled trial of chlorthalidone and bone loss in elderly women.

Abstract: Employing a double-masked, prospective design, bone loss at three skeletal sites has been monitored among 113 postmenopausal women participating in a placebo-controlled trial of the thiazide-like diuretic chlorthalidone for treatment of systolic hypertension. The mean duration of chlorthalidone use was 2.6 years, at doses of 12.5-25 mg/day. Compared with placebo use, chlorthalidone use was associated with significant reductions in annual bone loss rates. Non-use of chlorthalidone was associated with bone loss at the calcaneus (-0.56% per year) and the proximal radius (-0.91% per year); borderline bone gain was observed at the distal radius (+0.39%). In contrast, chlorthalidone use was associated with bone gain at the calcaneus (+0.44% per year) and the distal radius (+1.51% per year); proximal radius bone loss was significantly reduced to -0.32% per year. The average increment for three appendicular sites was +0.9% per year. These data support a causal relationship between chlorthalidone use and reduced bone loss.

Prevention of early postmenopausal bone loss using low doses of conjugated estrogens and the non-hormonal, bone-active drug ipriflavone.

Abstract: Hormone replacement therapy is the optimal therapeutic choice for postmenopausal syndrome. While low doses of estrogens (0.3 mg/day of conjugated estrogens) can counteract neurovegetative menopausal symptoms, higher doses (0.625 mg/day of conjugated estrogens) are required to prevent bone loss in postmenopausal women. Experimental and clinical studies have shown that ipriflavone, a non-hormonal isoflavone derivative, is effective in the prevention and treatment of postmenopausal osteoporosis. The aim of the present investigation was to evaluate the efficacy and toler-ability of ipriflavone and very low doses of equine conjugated estrogens on bone loss in early postmenopausal women. Eighty-three healthy postmenopausal women (50.3±0.7 years) were enrolled for this 1-year multicenter study. All subjects were randomly allocated to receive: double placebo (n=24; group A), placebo plus conjugated equine estrogens 0.30 mg/day (n=31; group B) or conjugated equine estrogens 0.30 mg/day plus oral ipriflavone 200 mg tris in die at meals (n=28; group C), according to a double-masked design. Among women who completed the treatment period (valid completers), those of group A showed a progressive decrease in forearm bone density (FBD; measured by dual photon absorptiometry) that reached 1.7% after 12 months. The women in group B maintained their FBD in the first 6 months of treatment but, at the end of the study, showed a bone loss of 1.4% compared with basal values. By contrast, women in group C showed a significant increase in FBD after 1 year of treatment (+5.6%;p<0.01). Bothvalid completers andintention to treat analyses revealed a significant difference (p<0.05) between group A and group C over the study period. None of the treatments produced significant changes of biochemical markers of bone turnover, while hot flushes and other climacteric symptoms were significantly reduced after the sixth month of treatment in women receiving estrogens. Adverse events were generally mild, and did not differ among the groups. The results of this study suggest that low doses of estrogens combined with ipriflavone could represent a new therapeutic approach to the treatment of the postmenopausal syndrome.