Effects of long-term alendronate treatment on bone mineralisation, resorption parameters and biomechanics of single human vertebral trabeculae.

Due to their well-established fracture risk reduction, bisphosphonates are the most frequently used therapeutic agent to treat osteoporosis. Bisphosphonates reduce fracture risk by suppressing bone resorption, but the lower bone turnover could have a negative impact on bone quality at the tissue level. Here, we directly assess the structural and mechanical characteristics of cancellous bone from the lumbar vertebrae (L5) in non-treated osteoporotic controls (n=21), mid-term alendronate-treated osteoporotic patients (n=6), and long-term alendronate-treated osteoporotic patients (n=7). The strength and toughness of single trabeculae were evaluated, while the structure was characterised through measurements of microdamage accumulation, mineralisation distribution, and histological indices. The alendronate-treated cases had a reduced eroded surface (ES/BS, p<0.001) and a higher bone mineralisation in comparison to non-treated controls (p=0.037), which is indicative of low turnover associated with treatment. However, the amount of microdamage and the mechanical properties were similar among the control and treatment groups. As the tissue mineral density (TMD) increased significantly with alendronate treatment compared to non-treated osteoporotic controls, the reduction in resorption cavities could counterbalance the higher TMD allowing the alendronate-treated bone to maintain its mechanical properties and resist microdamage accumulation. A multivariate analysis of the possible predictors supports the theory that multiple factors (e.g., body mass index, TMD, and ES/BS) can impact the mechanical properties. Our results suggest that long-term alendronate treatment shows no adverse impact on mechanical cancellous bone characteristics.

Accuracy of trabecular structure by HR-pQCT compared to gold standard µCT in the radius and tibia of patients with osteoporosis and long-term bisphosphonate therapy.

UNLABELLED: Despite an increasing use of high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate bone morphology in vivo, there are reservations about its applicability in patients with osteoporosis and antiresorptive therapy. This study shows that HR-pQCT provides acceptable in vivo accuracy for bone volume fraction (BV/TV) in patients with osteoporosis and bisphosphonate (BP) treatment. INTRODUCTION: The primary aim was to analyze agreement of trabecular structure between HR-pQCT and gold standard microtomography (µCT) in patients with osteoporosis and long-term BP therapy. METHODS: In the BioAsset study, we analyzed cadaver radii and tibiae of 34 postmenopausal females (81.1 ± 7.1 years) with osteoporosis (no BP n = 22, 1-5 years BP n = 5, >5 years BP n = 7). Two HR-pQCT protocols (patient-mode and µCT-mode) were compared with gold standard µCT after image registration. Undecalcified histological sections were obtained to quantify nonmineralized bone matrix. Bland-Altman plots illustrated methodological agreement. Multiple regression analysis was used to test for variables associated with method agreement. RESULTS: In the radius and tibia, patient-mode HR-pQCT derived indices including bone volume fraction, trabecular number, and trabecular separation correlated well with gold standard µCT (R(2) = 0.78 - 0.88) except for trabecular thickness (R(2) = 0.11). Bland-Altman plots illustrated adequate agreement for bone volume fraction. Lower agreement of trabecular number and trabecular separation improved with decreasing structural impairment at the tibia only. Trabecular thickness was not appropriately assessed with HR-pQCT at both skeletal sites. Higher agreement for bone volume fraction was associated with increasing tissue mineral density in the tibia. CONCLUSIONS: HR-pQCT provides acceptable in vivo accuracy for BV/TV in patients with osteoporosis and BP treatment. Higher TMD was associated with higher BV/TV accuracy in vivo. Overall, methodological agreement got less accurate with increasing structural impairment in the tibia.

International variation in proximal femur bone mineral density.

UNLABELLED: We observed higher proximal femur bone mineral density (BMD) in European women compared to average values derived from US Caucasian women in the National Health and Nutrition Examination Survey (NHANES) study. Across European centres, Parisian women had lower proximal femur BMD compared to women from Kiel or Sheffield. INTRODUCTION: Proximal femur BMD of US adults (NHANES III) may not accurately reflect that of European women. We examined the heterogeneity of BMD across European and US Caucasian women and across different European populations. METHODS: Proximal femur BMD was measured in women ages 20-39 years (n=258) and 55-79 years (n=1,426) from three European centres. Cross-calibrated BMD for total hip, femoral neck, trochanter and intertrochanter were examined. International variation in BMD was assessed by comparing means and SDs in the European data with those from the US NHANES III study. European populations were stratified into 5-year age bands to establish individual centre reference intervals. Between-centre differences were assessed using ANOVA and post hoc Fisher's least significant difference tests. RESULTS: European women had higher BMD than US women: The differences were 7.1% to 14.2% (p<0.001) and 0% to 3.9% (p<0.05) in the older and younger women, respectively. Standard deviations for BMD at the different sites were comparable to those for US women. Among older, but not younger European women, proximal femur BMD was significantly lower in French women (Paris) than in women from Germany (Kiel) or the UK (Sheffield) (difference=5.0% to 9.6%, p<0.05). CONCLUSIONS: International variation in hip BMD does exist, with international and between-centre differences being less evident at the femoral neck.

Geographic and other determinants of BMD change in European men and women at the hip and spine. a population-based study from the Network in Europe for Male Osteoporosis (NEMO).

INTRODUCTION: While the determinants of BMD change have been studied in women, there have been few longitudinal studies in men. As part of the Network in Europe for Male Osteoporosis (NEMO) study, data were analysed from 1337 men and 1722 women aged 50-86y (mean=67 years) from 13 centres across Europe to assess determinants of BMD change and between-gender contrasts. METHODS: BMD was measured at the femoral neck, trochanter and/or L2-L4 spine on 2 occasions 0.8-8 years apart (mean=3.5 years) using DXA densitometers manufactured by Hologic (n=6), Lunar (n=5) and Norland (n=2). Each was cross-calibrated using the European Spine Phantom and annual rates of BMD change (g/cm(2)/year) were calculated from the standardised paired BMD values. The EPOS risk factor questionnaire was administered at baseline. RESULTS: In multivariate linear regression models, there were large between centre differences in the mean rates of BMD change in all 3 sites for both genders (P<0.0001) with the standard deviation of the between centre heterogeneity in the adjusted means being 0.005 g/cm(2)/year at the femoral neck. The overall adjusted mean annual rates of BMD change in g/cm(2)/year (95% CI) pooled across centres by random effects meta-analysis in men were: femoral neck -0.005 (-0.009, -0.001); trochanter -0.003 (-0.006, -0.001); and spine 0.000 (-0.004, 0.004). In women the respective estimates were: -0.007 (-0.009, -0.005); -0.004 (-0.006, -0.003); and -0.005 (-0.008, -0.001). The I(2) statistic for heterogeneity was between 81% and 94%, indicating strong evidence of between centre heterogeneity. Higher baseline BMD value was associated with subsequent greater decline in BMD (P<0.001). Preserved BMD was associated with higher baseline body weight in all 3 sites in men (P<0.012) but not in women. Weight gain preserved BMD (P<0.039) in all 3 sites for both genders, except the male spine. Increasing age was associated with faster BMD decline at the trochanter in both genders (P<0.026) and with a slower rate of decline at the female spine (P=0.002). Effects of lifestyle, physical activity, medications, and reproductive factors were not consistent across sites or between genders. CONCLUSION: These results show major geographic variations in rates of BMD change in men and women over 50 years of age across diverse European populations and demonstrate that body weight and weight gain are key determinants of BMD change in men.

Imaging of trabecular bone structure in osteoporosis.

Osteoporosis is a metabolic bone disorder that is characterized by reduced bone mass and a deterioration of bone structure which results in an increased fracture risk. Since the disease is preventable, diagnostic techniques are of major importance. Standard techniques determine bone mineral density, whereas some of the newer techniques focus on trabecular structure. This article reviews structure analysis techniques in the diagnosis of osteoporosis. Imaging techniques applied to the assessment of trabecular bone structure include conventional radiography, magnification radiography, high-resolution CT (HRCT) and high-resolution MR imaging (HRMRI). The best results were obtained using high-resolution tomographic techniques. The highest spatial resolutions in vivo were achieved using HRMRI. The most common texture analysis techniques that have been used are morphological parameters (analogous to bone histomorphometry). Fractal dimension, co-occurrence matrices, mathematical filter techniques and autocorrelation functions are more complex techniques. Most of the studies evaluating structure analysis show that texture parameters and bone mineral density both predict bone strength and osteoporotic fractures, and that combining both techniques yields the best results in the diagnosis of osteoporosis.

Mild versus definite osteoporosis: comparison of bone densitometry techniques using different statistical models.

The purpose of this investigation was to determine the ability of three bone densitometry techniques to discriminate subjects with mild vertebral deformities from those with definite compression fractures. We determined bone mineral density (BMD) in 68 postmenopausal women by quantitative computed tomography (QCT) and dual-photon absorptiometry (DPA) of the spine, as well as single-photon absorptiometry (SPA) of the radius. Forty four individuals were classified as having mild deformities of the spine and 24 were considered to have definite vertebral compressions. Several statistical approaches were used to compare these subgroups and to estimate the relative risk of vertebral fracture. Included among these were percent decrements and zeta-scores, ROC curves, odds ratio estimations, and logistic regression analysis. Individuals with definite vertebral fractures had lower bone mineral density at all sites, but measurement of radial compact bone by SPA failed to reach significance. Using ROC analysis to distinguish mild deformities from true compressions, we found that measurement of spinal trabecular bone by QCT to be the most sensitive discriminator; although measurement of spinal integral bone by DPA also gave satisfactory discrimination, whereas assessment of radial compact bone did not adequately differentiate patients with mild deformities from those with definite compressions. Likewise, we found determination of spinal trabecular bone to be the most robust predictor of relative risk of definite fracture using either odds ratios or logistic regression analysis. Measurement of BMD in the peripheral cortical skeleton offered no predictive power for true vertebral fracture. We concluded that direct assessment of the spine, particularly of the trabecular portion, offered the strongest discrimination and relative risk prediction for definite osteoporotic fractures compared with milder forms of this condition.

New developments in bone densitometry.

The new development in QCT and DPA will reduce the time of diagnostic studies to several minutes and improve precision severalfold. It may therefore be feasible to do selective screening procedures at costs as low as $50 to $100. Thus, these advances in QCT and DPA are promising to provide capabilities that have been needed in bone densitometry--high reliability, excellent patient throughput, and services at economical levels.

Models of spinal trabecular bone loss as determined by quantitative computed tomography.

Noninvasive bone densitometry techniques have significantly improved our understanding of the pattern and magnitude of bone loss over the life span. Quantitative computed tomography (QCT) is capable of selectively measuring highly labile trabecular bone in the central portion of the vertebrae. Trabecular bone mineral density (mg/ml) was determined in 538 healthy women ranging in age from 20 to 80 using GE CT/T scanners at 80 kVp. Various statistical regressions were performed for the entire population to describe the general pattern of bone loss from the spine; a cubic model (r = -0.69, SEE = 26.0 mg/ml) was found to be statistically superior (p less than 0.01) to linear, quadratic, or exponential models. An average bone loss was approximated from these regression analyses with a yearly absolute rate of -2.02 +/- 0.097 mg/ml per year (p less than 0.0001). The average rate of change for premenopausal women was -0.45 mg/ml per year (p less than 0.05), for perimenopausal women was -4.39 mg/ml per year (p less than 0.0001) and for postmenopausal women was -1.99 mg/ml per year (p less than 0.0001). QCT values were also stratified into 5 and 10 year age groups and analyzed separately for pre- and postmenopausal women. The 5 and 10 year interval stratification revealed no identifiable bone density decrements prior to midlife using analysis of variance statistical methods; significant losses of bone mineral density were noted to correspond with the usual time of menopause and to continue into old age. Various two-phase regressions were employed using age and menstrual status to improve the description of age- and menopause-related bone loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Appropriate use of bone densitometry.

The authors discuss current capabilities of three common bone densitometry techniques--single photon absorptiometry, dual photon absorptiometry, and quantitative computed tomography--and potential capabilities of new innovations of each of these techniques. They believe that use of bone densitometry is valid in the following four clinical applications and recommend its usage to (a) assess patients with metabolic diseases known to affect the skeleton, (b) assess perimenopausal women for initiation of estrogen replacement therapy, (c) establish a diagnosis of osteoporosis or assess its severity in the context of general clinical care, and (d) monitor the efficacy of treatment interventions or the natural course of disease.

Quantitative computed tomography in assessment of osteoporosis.

Computed tomography (CT) has been widely investigated and applied in recent years as a means for noninvasive quantitative bone mineral determination. The usefulness of computed tomography for measurement of bone mineral lies in its ability to provide a quantitative image and, thereby, measure trabecular, cortical, or integral bone, centrally or peripherally. For measuring the spine, the potential advantages of quantitative computed tomography (QCT) over dual-photon absorptiometry (DPA) are its capability for precise three-dimensional anatomic localization providing a direct density measurement, and its capability for spatial separation of highly responsive cancellous bone from less responsive compact bone. Currently, QCT vertebral mineral determination has been implemented at over 800 sites encompassing a wide geographic distribution and a wide array of commercial scanners. With a world-wide distribution of approximately 8,000 advanced CT body scanners, the capability now exists for widespread application of vertebral bone mineral determination by quantitative computed tomography. These QCT techniques for vertebral mineral determination have been used to study skeletal changes in osteoporosis and other metabolic bone diseases. Longitudinal and cross-sectional bone mass measurements have been obtained at the University of California at San Francisco (UCSF) in over 3,000 patients seen clinically or on research protocols. The results presented here illustrate the use of QCT spinal mineral measurement in the delineation of normal age-related bone loss, in the evaluation of estrogen effects on bone, in the assessment of fracture threshold and risk, and in the study of the effects of various exercise regimens on bone mineral and the determination of relationships to other techniques of bone mineral measurement. The laboratory and clinical results presented herein indicate that QCT provides a reliable means to evaluate and monitor the many forms of osteoporosis and the various interventions aimed at ameliorating this condition. The greatest advantages of spinal QCT for noninvasive bone mineral measurement lie in the high precision of the technique, the high sensitivity of the vertebral trabecular measurement site, and the potential for widespread application.