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Quantitative ultrasound (QUS) measurements of trabecular bone are a useful tool for the assessment of osteoporotic fracture risk. However, cortical bone properties (e.g. porosity) have an impact on bone strength as well and thus current research is focused on QUS assessment of cortical bone properties. Simulation studies of ultrasound propagation through cortical bone indicate that anisotropy, calculated from the ratio of the velocities in axial and tangential directions, is correlated with porosity. However, this relationship is affected by error sources, specifically bone surface curvature and variability of probe positioning. With the aim of in vivo estimation of cortical porosity a new ultrasound device was developed, which sequentially measures velocities in 3 different directions (axial = 0° and ±37.5°) using the axial transmission method. Measurements on planar porosity phantoms (0–25%) were performed to confirm the results of the afore mentioned simulation studies. Additionally, measurements on cylindrical phantoms without pores (min. radius = 34 mm for strongest curvature) were performed to estimate the influence of surface curvature on velocity measurements (the tibia bone surface is fairly flat but may show surface curvature in some patients). The velocities in the axial and ±37.5° directions were used to calculate an anisotropy index. The velocities measured on the porosity phantoms showed a decrease by −6.3 ± 0.2 m/s and −10.1 ± 0.2 m/s per percent increase in porosity in axial and ±37.5° directions, respectively. Surface curvature had an effect on the velocities measured in ±37.5° directions which could be minimized by a correction algorithm resulting in an error of 5 m/s. The anisotropy index could be used to estimate porosity with an accuracy error of 1.5%. These results indicate that an estimation of porosity using velocity measurements in different directions might be feasible, even in bones with curved surface. These results obtained on phantom material indicate that the approach tested may be suited for porosity measurements on human tibia bone. [ABSTRACT FROM AUTHOR]

This is part 2 of a core chapter of the forthcoming Report on Bone Densitometry commissioned by the International Commission on Radiation Units (ICRU). It is written with the aim to review definitions of quantities and units used in bone densitometry research and to describe parameters and methods that can be used to compare and standardize densitometric equipment and measurements. Part 2 of this chapter contains the section on fracture risk. Building on concepts of risk assessment, including risk ratios and odds ratios, we review statistical concepts commonly used in cross-sectional and prospective fracture studies. Performance measures are defined that allow a comparison of the ability of densitometry techniques to assess fracture risk. The methods of discriminant analysis, logistic regression, Poisson regression models, and the Cox proportional hazard model are presented and compared. In addition, statistical concepts to characterize risk for the individual patient are reviewed. [ABSTRACT FROM AUTHOR]

Summary: We reviewed the experimental and clinical evidence that hip bone strength estimated by BMD and/or finite element analysis (FEA) reflects the actual strength of the proximal femur and is associated with hip fracture risk and its changes upon treatment. Introduction: The risk of hip fractures increases exponentially with age due to a progressive loss of bone mass, deterioration of bone structure, and increased incidence of falls. Areal bone mineral density (aBMD), measured by dual-energy X-ray absorptiometry (DXA), is the most used surrogate marker of bone strength. However, age-related declines in bone strength exceed those of aBMD, and the majority of fractures occur in those who are not identified as osteoporotic by BMD testing. With hip fracture incidence increasing worldwide, the development of accurate methods to estimate bone strength in vivo would be very useful to predict the risk of hip fracture and to monitor the effects of osteoporosis therapies. Methods: We reviewed experimental and clinical evidence regarding the association between aBMD and/orCT-finite element analysis (FEA) estimated femoral strength and hip fracture risk as well as their changes with treatment. Results: Femoral aBMD and bone strength estimates by CT-FEA explain a large proportion of femoral strength ex vivo and predict hip fracture risk in vivo. Changes in femoral aBMD are strongly associated with anti-fracture efficacy of osteoporosis treatments, though comparable data for FEA are currently not available. Conclusions: Hip aBMD and estimated femoral strength are good predictors of fracture risk and could potentially be used as surrogate endpoints for fracture in clinical trials. Further improvements of FEA may be achieved by incorporating trabecular orientations, enhanced cortical modeling, effects of aging on bone tissue ductility, and multiple sideway fall loading conditions. [ABSTRACT FROM AUTHOR]

Introduction Established scores estimate 10-year fracture risk in osteoporosis to assist with treatment recommendations. This study compared the risk probabilities of major osteoporotic and hip fractures calculated by the FRAX tool with those of the DVO score, established in German-speaking countries. Material and Methods This seven-year retrospective study analyzed data of 125 male patients (mean age: 59.2±10.7 years) evaluated for osteoporosis. For the DVO score, the therapy threshold of>30% for vertebral and hip fractures suggested by DVO guidelines was implemented. We calculated fracture risks based on FRAX scores with aBMD and applied a common therapy threshold of≥3% for hip fracture and subsequently determined the "DVO-equivalent risk level" for FRAX-based assessment that would identify as many male patients as identified by the DVO score. Results Based on DVO score, 60.0% of patients had a 10-year risk of hip and vertebral fractures>30%. The recommendations for individuals based on FRAX scores for hip fracture with aBMD with risk≥3% overlapped with those based on DVO score in 36% of patients. Patients identified for treatment only by DVO score presented a higher percentage of spine fractures (65 vs. 41%). The thresholds for this "DVO-equivalent risk level" for 'FRAX with aBMD' was estimated to be≥6.7% for major osteoporotic fracture and≥2.1% for hip fracture. This study demonstrates that the DVO score was more sensitive than the FRAX score for patients with prevalent spinal fractures. We suggest considering the appropriate score and therapy threshold carefully in the daily care of male patients. [ABSTRACT FROM AUTHOR]

Highlights: [•] We developed an ultrasound probe for measurements at the tibial shaft. [•] The device can reproducibly measure the anisotropy of sound velocity in cortical bone. [•] Sound velocity and anisotropy are expected to be indicators of bone strength. [•] Anisotropies of two excised human tibiae were significantly different. [ABSTRACT FROM AUTHOR]

The treatment of osteoporotic patients with teriparatide is associated with a significant increase in bone formation and gain of bone mass. The purpose of this post hoc analysis was to determine if the cross-sectional area (CSA) of the spinal canal and the vertebral body is affected by teriparatide treatment. Narrowing of the spinal canal might represent a safety problem, while widening of the vertebral CSA might improve mechanical stability. High-resolution computed tomography (HRCT) scans of vertebra T12 were obtained at baseline and after 6, 12, and 24 months of teriparatide treatment (20 microg/day) from 44 postmenopausal women with established osteoporosis participating in the prospective, randomized EUROFORS study. The CSA of the spinal canal did not decrease but increased marginally by 0.9% (2.6 mm(2)) over 24 months (P < 0.001), with a range from -0.5% (-2 mm(2)) to 3.1% (+8 mm(2)). Even when analyzing the spinal CSA on a slice-by-slice basis, no clinically relevant narrowing of the spinal canal was observed. For vertebral bodies, the CSA increased by 0.7% (5.7 mm(2)) over 24 months (P < 0.001), with a range from -0.4% (-3 mm(2)) to 1.6% (+14 mm(2)). Our data do not provide evidence for safety concerns regarding spinal canal narrowing. On the other hand, the increases observed for vertebral CSA apparently also only minimally contribute to the mechanical strengthening of the vertebral body under teriparatide treatment. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) measured with dual energy X-ray absorptiometry (DXA) techniques is the current gold standard for osteoporotic fracture risk prediction. Quantitative ultrasound (QUS) techniques in transmission measurements are, however, increasingly recognized as an alternative approach. It is feasible to select different QUS methods, one type being optimized to assess microarchitectural properties of bone structure and another to assess BMD. Broadband ultrasonic attenuation (BUA) and ultrasonic velocity (UV) measured on the proximal human femur have been shown to be both significantly correlated with BMD. However, a great diversity of algorithms has been reported to measure the time-of-flight used to derive UV values. The purpose of this study was to determine which procedure results in the optimal BMD prediction at the proximal femur from ultrasound measurements. Thirty-eight excised human femurs were measured in transmission with a pair of focused 0.5-MHz central frequency transducers. Two-dimensional scans were performed and radiofrequency (RF) signals were recorded digitally at each scan position. BUA was estimated and eight different signal processing techniques were performed to estimate UV. For each signal-processing technique UV was compared to BMD. We show that the best prediction of BMD was obtained with signal-processing techniques taking into account only the first part of the transmitted signal (r2BMD-SOS = 0.86). Moreover, we show that a linear multiple regression using both BUA and speed of sound (SOS) and applied to site-matched regions of interest improved the accuracy of BMD predictions (r2BMD-SOS/BUA = 0.95). Our results demonstrate that selecting specific signal-processing methods for QUS variables allows optimal assessment of BMD. Correlation is sufficiently high that this specific QUS method can be considered as a good surrogate of BMD. [ABSTRACT FROM AUTHOR]

Abstract: Quantitative ultrasound has been recognized as a useful tool for fracture risk prediction. Current measurement techniques are limited to peripheral skeletal sites. Our objective was to demonstrate the in vitro feasibility of ultrasonic velocity measurements on human proximal femur and to investigate the relationship between velocity and bone mineral density (BMD). Sound velocity images were computed from 2-D scans performed on 38 excised human femurs in transmission at 0.5 MHz. Different regions-of-interest were investigated. Dual x-ray absorptiometry scans have been achieved for BMD measurements in site-matched regions. Our study demonstrates the feasibility of ultrasonic velocity measurements at the hip with reasonable precision (coefficient of variation of 0.3%). The best prediction of BMD was reached in the intertrochanter region (r2 = 0.91, p &#60; 10−4), with a residual error of 0.06 g/cm2 (10%). Because BMD measured at the femur is the best predictor of hip fracture risk, the highly significant correlation and small residual error found in this study suggest that speed of sound measurement at the femur might be a good candidate for hip fracture risk prediction. (E-mail: Frederic.padilla@lip.bhdc.jussieu.fr) [Copyright &y& Elsevier]

Summary The Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study investigated the effectiveness of a two-step screening program for osteoporosis in women. We found no overall reduction in fractures from systematic screening compared to the current case-finding strategy. The group of moderate- to high-risk women, who accepted the invitation to DXA, seemed to benefit from the program. Introduction The purpose of the ROSE study was to investigate the effectiveness of a two-step population-based osteoporosis screening program using the Fracture Risk Assessment Tool (FRAX) derived from a self-administered questionnaire to select women for DXA scan. After the scanning, standard osteoporosis management according to Danish national guidelines was followed. Methods Participants were randomized to either screening or control group, and randomization was stratified according to age and area of residence. Inclusion took place from February 2010 to November 2011. Participants received a self-administered questionnaire, and women in the screening group with a FRAX score ≥ 15% (major osteoporotic fractures) were invited to a DXA scan. Primary outcome was incident clinical fractures. Intention-to-treat analysis and two per-protocol analyses were performed. Results A total of 3416 fractures were observed during a median follow-up of 5 years. No significant differences were found in the intention-to-treat analyses with 34,229 women included aged 65–80 years. The per-protocol analyses showed a risk reduction in the group that underwent DXA scanning compared to women in the control group with a FRAX ≥ 15%, in regard to major osteoporotic fractures, hip fractures, and all fractures. The risk reduction was most pronounced for hip fractures (adjusted SHR 0.741, p = 0.007). Conclusions Compared to an office-based case-finding strategy, the two-step systematic screening strategy had no overall effect on fracture incidence. The two-step strategy seemed, however, to be beneficial in the group of women who were identified by FRAX as moderate- or high-risk patients and complied with DXA. [ABSTRACT FROM AUTHOR]

Summary: Population-based screening for osteoporosis is still controversial and has not been implemented. Non-participation in systematic screening was evaluated in 34,229 women age 65-81 years. Although participation rate was high, non-participation was associated with comorbidity, aging other risk factors for fractures, and markers of low social status, e.g., low income, pension, and living alone. A range of strategies is needed to increase participation, including development of targeted information and further research to better understand the barriers and enablers in screening for osteoporosis. Introduction: Participation is crucial to the success of a screening program. The objective of this study was to analyze non-participation in Risk-stratified Osteoporosis Strategy Evaluation, a two-step population-based screening program for osteoporosis. Methods: Thirty-four thousand two hundred twenty-nine women aged 65 to 81 years were randomly selected from the background population and randomized to either a screening group (intervention) or a control group. All women received a self-administered questionnaire designed to allow calculation of future risk of fracture based on FRAX. In the intervention group, women with an estimated high risk of future fracture were invited to DXA scanning. Information on individual socioeconomic status and comorbidity was obtained from national registers. Results: A completed questionnaire was returned by 20,905 (61%) women. Non-completion was associated with older age, living alone, lower education, lower income, and higher comorbidity. In the intervention group, ticking 'not interested in DXA' in the questionnaire was associated with older age, living alone, and low self-perceived fracture risk. Women with previous fracture or history of parental hip fracture were more likely to accept screening by DXA. Dropping out when offered DXA, was associated with older age, current smoking, higher alcohol consumption, and physical impairment. Conclusions: Barriers to population-based screening for osteoporosis appear to be both psychosocial and physical in nature. Women who decline are older, have lower self-perceived fracture risk, and more often live alone compared to women who accept the program. Dropping out after primary acceptance is associated not only with aging and physical impairment but also with current smoking and alcohol consumption. Measures to increase program participation could include targeted information and reducing physical barriers for attending screening procedures. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0 IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+ 50.1%, p = 0.001) and Ct.Po (+ 22.9%, p = 0.004), as well as to reduced mechanical competence (max. stress: − 14.2%, p = 0.041, toughness: − 29.7%, p = 0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R 2 = 0.41, p < 0.001, Ct.Po: R 2 = 0.34, p = 0.003) and HbA1c (NEG: R 2 = 0.42, p < 0.001, Ct.Po: R 2 = 0.28, p = 0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R 2 = 0.21, p = 0.023, yield stress: R 2 = 0.17, p = 0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats. Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75 μg/kg PTH (1–84) or vehicle 5 days per week over 12 weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence. Diabetes increased Ct.Po (vertebra (vert): + 40.6%, femur (fem): + 15.5% vs. ND group, p < 0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (− 73% vs untreated group, p < 0.05), and increased femoral NEG in the DB vs. ND groups (+ 63%, p < 0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (− 22%) and toughness (− 42%) were observed in the DB vs. ND group (p < 0.05). PTH improved maximum strain in the vertebra of the ND animals (+ 21%, p < 0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+ 21%) and toughness (+ 28%) in ND and decreased femoral maximum stress (− 13%) and toughness (− 27%) in the DB animals (treated vs. untreated, p < 0.05). Ct.Po correlated negatively with maximum stress (fem: R = − 0.35, p < 0.05, vert: R = − 0.57, p < 0.01), maximum strain (fem: R = − 0.35, p < 0.05, vert: R = − 0.43, p < 0.05) and toughness (fem: R = − 0.34, p < 0.05, vert: R = − 0.55, p < 0.01), and NEG correlated negatively with toughness at the femur (R = − 0.34, p < 0.05) and maximum strain at the vertebra (R = − 0.49, p < 0.05). Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs cross-linking. Optimal treatment regimens must address both improvements of bone mass and glycemic control in order to successfully reduce diabetic bone fragility. This article is part of a Special Issue entitled “Bone and diabetes”. [ABSTRACT FROM AUTHOR]

Zucker Diabetic Fatty (ZDF) rats represent an established model of type 2 diabetes mellitus (T2DM) and display several features of human diabetic bone disease, including impaired osteoblast function, decreased bone strength, and delayed bone healing. Here, we determined whether glycemic control by insulin treatment prevents skeletal complications associated with diabetes. Subcritical femur defects were created in diabetic (fa/fa) and non-diabetic (+/+) ZDF rats. Diabetic rats were treated once daily with long-lasting insulin glargin for 12 weeks for glycemic control. Insulin treatment successfully maintained serum levels of glycated hemoglobin, while untreated diabetic rats showed a 2-fold increase. Trabecular and cortical bone mass measured by μCT were decreased in diabetic rats. Insulin treatment increased bone mass of the cortical, but not of the trabecular bone compartment. Dynamic histomorphometry revealed a lower bone formation rate at the trabecular and periosteal cortical bone in diabetic animals and decreased serum procollagen type 1 N-terminal propeptide (P1NP, − 49%) levels. Insulin treatment partially improved these parameters. In T2DM, serum levels of tartrate-resistant acid phosphatase (TRAP, + 32%) and C-terminal telopeptide (CTX, + 49%) were increased. Insulin treatment further elevated TRAP levels, but did not affect CTX levels. While diabetes impaired bone defect healing, glycemic control with insulin fully reversed these negative effects. In conclusion, insulin treatment reversed the adverse effects of T2DM on bone defect regeneration in rats mainly by improving osteoblast function and bone formation. This article is part of a Special Issue entitled Bone and diabetes. [ABSTRACT FROM AUTHOR]

Summary: The correlations between the failure load of 20 T12 vertebral bodies, their patient-mode high-resolution peripheral quantitative computed tomography (HR-pQCT) indices, and the L1 areal bone mineral density (aBMD) were investigated. For the prediction of the T12 vertebral failure load, the T12 HR-pQCT microarchitectural parameters added significant information to that of L1 aBMD and to that of cortical BMD, but not to that of T12 vertebral BMD and not to that of T12 trabecular BMD. Introduction: HR-pQCT is a new in vivo imaging technique for assessing the three-dimensional microarchitecture of cortical and trabecular bone at the distal radius and tibia. But little is known about this technique in the direct measurement of vertebral body. Methods: Twenty female donors with the mean age of 80.1 (7.6) years were included in the study. Dual X-ray absorptiometry of the lumbar spine and femur was performed. The spinal specimens (T11/T12/L1) were dissected, scanned using HR-pQCT scanner, and mechanically tested under 4° wedge compression. The L1 aBMD, T12 patient-mode HR-pQCT indices, and T12 vertebral failure loads were analyzed. Results: For the prediction of vertebral failure load, the inclusion of BV/TV into L1 aBMD was the best model ( R = 0.52), Tb.N and Tb.Sp added significant information to the L1 aBMD and to the cortical BMD, but none of the vertebral microarchitectural parameters yielded additional significant information to the trabecular BMD (or BV/TV) and to the vertebral BMD. Conclusion: Vertebral microarchitectural parameters obtained from the patient-mode HR-pQCT analysis provide significant information on bone strength complementary to that of aBMD and to that of cortical BMD, but not to that of vertebral BMD and not to that of trabecular BMD. [ABSTRACT FROM AUTHOR]

Although the effect of age on body composition has been intensively discussed during the past 20 years, we do not have a uniform definition of sarcopenia. A suitable definition of low, lean body mass should be based on magnetic resonance imaging (MRI) estimates of muscle mass. Using recent MRI data of a population of 446 healthy free-living Caucasian volunteers (247 females, 199 males) age 18-78 years, a low skeletal muscle mass and sarcopenia were defined as a skeletal muscle mass >1 and >2 s.d. below the mean value obeserved in younger adults at age 18-39 years. The cutoffs for low muscle mass according to the skeletal muscle index (skeletal muscle mass/(height)2) or the appendicular skeletal muscle mass index (skeletal muscle mass of the limbs/(height)2) were 6.75 or 4.36 kg/m2 for females and 8.67 or 5.54 kg/m2 for males, respectively. On the basis of these cutoffs, prevalences of sarcopenia in the group of adults at >60 years are calculated to be 29% in females and 19.0% in males. Faced with different sarcopenic phenotypes (that is, sarcopenia related to frailty and osteopenia; sarcopenic obesity related to metabolic risks; cachexia related to wasting diseases), future definitions of sarcopenia should be extended to the relations between (i) muscle mass and adipose tissue and (ii) muscle mass and bone mass. Suitable cutoffs should be based on the associations between estimates of body compositions and metabolic risks (for axample, insulin resistance), inflammation and muscle function (that is, muscle strength). [ABSTRACT FROM AUTHOR]

Summary: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients. [ABSTRACT FROM AUTHOR]

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations. [ABSTRACT FROM AUTHOR]

Background:Although weight cycling is frequent in obese patients, the adverse consequences on body composition and an increased propensity to weight gain remain controversial.Objective:We investigated the effect of intentional weight loss and spontaneous regain on fat distribution, the composition of lean mass and resting energy expenditure (REE).Design:Weight regainers (30% of loss, n=27) and weight-stable subjects (within <±20% of weight change, n=20) were selected from 103 overweight and obese subjects (body mass index 28-43 kg m−2, 24-45 years) who passed a 13-week low-calorie diet intervention. REE and body composition (by densitometry and whole-body magnetic resonance imaging) were examined at baseline, after weight loss and at 6 months of follow-up.Results:Mean weight loss was −12.3±3.3 kg in weight-stable subjects and −9.0±4.3 kg in weight regainers (P<0.01). Weight regain was incomplete, accounting for 83 and 42% of weight loss in women and men. Regain in total fat and different adipose tissue depots was in proportion to weight regain except for a higher regain in adipose tissue of the extremities in women and a lower regain in extremity and visceral adipose tissue in men. In both genders, regain in skeletal muscle of the trunk lagged behind skeletal muscle regain at the extremities. In contrast to weight-stable subjects, weight regainers showed a reduced REE adjusted for changes in organ and tissue masses after weight loss (P<0.001).Conclusion:Weight regain did not adversely affect body fat distribution. Weight loss-associated adaptations in REE may impair weight loss and contribute to weight regain. [ABSTRACT FROM AUTHOR]

Summary: Vertebral fracture assessment (VFA) with densitometric devices uses less radiation than spinal radiography. We assessed risk of new vertebral fracture (VF) in women with baseline fracture identified on VFA using algorithm-based qualitative diagnosis. Women with VF had significantly greater risk of VF after 6 years compared to those without baseline fracture. Introduction: Prevalent VFs predict future fracture and are identifiable on vertebral fracture assessment (VFA) using bone densitometry devices. We have previously performed cross-sectional, but not longitudinal, VFA using the algorithm-based qualitative method (ABQ). We aimed to examine the prevalence and incidence of VF and test the association between prevalent and incident VF identified by ABQ VFA. Methods: We used ABQ to assess vertebral images obtained at baseline and 6 years (Hologic devices) in 674 women at ages 39 to 80 years participating in the Osteoporosis and Ultrasound Study. Criteria for prevalent and incident VF were endplate fracture, with/without cortical fracture. We compared proportions (chi-squared test) and characteristics (two-sample t tests and analysis of variance) of women with and without VF and calculated odds ratios for incident VF in women with prevalent VF (logistic regression). Results: Prevalent VF was identified in one premenopausal woman and 41 postmenopausal women. Incident VF was identified in 18 postmenopausal women. Odds ratios (95% CI) for incident VF in postmenopausal women with prevalent VF were 7.8 (2.8, 22.1) (unadjusted) and 4.3 (1.4, 13.7) (adjusted for age and bone mineral density, BMD). Women with prevalent or incident VF were older ( P < 0.01), with lower hip BMD ( P < 0.001) compared to women without VF. Conclusions: Population-based postmenopausal women had relatively low prevalence and incidence of VF analysed with the ABQ method applied to VFA. Women with prevalent fracture had a significantly greater risk of incident VF than women without prevalent fracture. [ABSTRACT FROM AUTHOR]

Background/Objective:In 1975, a Reference Man for the estimation of radiation doses without adverse health effects was created. However, during the past few decades, considerable changes in body weight and body composition were observed, as a result of which, new in vivo technologies of body composition analysis are now available. Thus, the Reference Man might be outdated as adequate standard to assess medication and radiation doses. The objective of this study was to compare body composition of an adult population with 1975 Reference Man data, thereby questioning its value as a suitable reference.Methods:Body composition was assessed in 208 healthy, Caucasian subjects (105 males, 103 females) aged 18-78 years with a body mass index range of 16.8-35.0 kg/m2. Fat mass (FM) and muscle mass (MM) were assessed by dual-energy X-ray absorptiometry, organ masses (OMs) were measured by magnetic resonance imaging.Results:There was a considerable variance in body weight and body composition. When compared with Reference Man, great differences in body composition were found. Men and women of the study population were heavier, taller and had more FM, MM and higher masses of brain, heart and spleen. These differences did not depend on age. Relationships between body weight and body composition were investigated by general linear regression models, whereby deviations in FM, MM and heart mass disappeared, whereas differences in brain and spleen mass persisted.Conclusions:Our data indicate the need of a modern Reference Man and thus a recalculation of medical radiation doses and medication. [ABSTRACT FROM AUTHOR]

A quantitative ultrasound (QUS) device for measurements at the proximal femur was developed and tested in vivo (Femur Ultrasound Scanner, FemUS). Hip fracture discrimination was as good as for DXA, and a high correlation with hip BMD was achieved. Our results show promise for enhanced QUS-based assessment of osteoporosis. Dual X-ray absorptiometry (DXA) at the femur is the best predictor of hip fractures, better than DXA measurements at other sites. Calcaneal quantitative ultrasound (QUS) can be used to estimate the general osteoporotic fracture risk, but no femoral QUS measurement has been introduced yet. We developed a QUS scanner for measurements at the femur (Femur Ultrasound Scanner, FemUS) and tested its in vivo performance. Using the FemUS device, we obtained femoral QUS and DXA on 32 women with recent hip fractures and 30 controls. Fracture discrimination and the correlation with femur bone mineral density (BMD) were assessed. Hip fracture discrimination using the FemUS device was at least as good as with hip DXA and calcaneal QUS. Significant correlations with total hip bone mineral density were found with a correlation coefficient R2 up to 0.72 and a residual error of about one half of a T-score in BMD. QUS measurements at the proximal femur are feasible and show a good performance for hip fracture discrimination. Given the promising results, this laboratory prototype should be reengineered to a clinical applicable instrument. Our results show promise for further enhancement of QUS-based assessment of osteoporosis. [ABSTRACT FROM AUTHOR]

Information on the pathophysiology of glucocorticoid-induced osteoporosis (010) is limited, since its clinical picture often reflects a combined effect of glucocorticoids (GC) and the treated systemic disease (i.e., inflammation and immobility). In 50 healthy adult (30-mo-old) primiparous Göttingen minipigs, we studied the short-term (8 mo, n = 30) and long-term (15 mo, n = 10) effect of GC on bone and mineral metabolism longitudinally and cross-sectionally compared with a control group (n = 10). All animals on GC treatment received prednisolone orally at a dose of 1.0 mg·kg body wt-1·day-1 for 8 wk and thereafter at 0.5 mg/kg body wt day-1. In the short term, GC reduced bone mineral density (BMD) at the lumbar spine by -47.5 ± 5.1 mg/cm³ from baseline (P < 0.001), which was greater (P < 0.05) than the loss [not significant (NS)] in the control group of -11.8 ± 12.6 mg/cm³. Calcium absorption decreased from baseline by -2,488 ± 688 mg/7 days (P < 0.001) compared with -1,380 ± 1,297 mg/7 days (NS) in the control group. Plasma bone alkaline phosphatase (BAP) decreased from baseline by -17.8 ± 2.2 U/l (P < 0.000), which was significantly different (P < 0.05) from the value of the control group of -1.43 ± 4.8 U/l. In the long term, the loss of BMD became more pronounced and bone mineral content (BMC), trabecular thickness, mechanical stability, calcium absorption, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and parathyroid hormone tended to be lower compared with the control group. There was a negative association between the cumulative dose of GC and BMD, which was associated with impaired osteoblastogenesis. In conclusion, the main outcomes after GC treatment are comparable to symptoms of GC-induced osteoporosis in human subjects. Thus the adult Göttingen miniature pig appears to be a valuable animal model for GC-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Objective:There are considerable differences in published prediction algorithms for resting energy expenditure (REE) based on fat-free mass (FFM). The aim of the study was to investigate the influence of the methodology of body composition analysis on the prediction of REE from FFM.Design:In a cross-sectional design measurements of REE and body composition were performed.Subjects:The study population consisted of 50 men (age 37.1±15.1 years, body mass index (BMI) 25.9±4.1 kg/m2) and 54 women (age 35.3±15.4 years, BMI 25.5±4.4 kg/m2).Interventions:REE was measured by indirect calorimetry and predicted by either FFM or body weight. Measurement of FFM was performed by methods based on a 2-compartment (2C)-model: skinfold (SF)-measurement, bioelectrical impedance analysis (BIA), Dual X-ray absorptiometry (DXA), air displacement plethysmography (ADP) and deuterium oxide dilution (D2O). A 4-compartment (4C)-model was used as a reference.Results:When compared with the 4C-model, REE prediction from FFM obtained from the 2C methods were not significantly different. Intercepts of the regression equations of REE prediction by FFM differed from 1231 (FFMADP) to 1645 kJ/24 h (FFMSF) and the slopes ranged between 100.3 kJ (FFMSF) and 108.1 kJ/FFM (kg) (FFMADP). In a normal range of FFM, REE predicted from FFM by different methods showed only small differences. The variance in REE explained by FFM varied from 69% (FFMBIA) to 75% (FFMDXA) and was only 46% for body weight.Conclusion:Differences in slopes and intercepts of the regression lines between REE and FFM depended on the methods used for body composition analysis. However, the differences in prediction of REE are small and do not explain the large differences in the results obtained from published FFM-based REE prediction equations and therefore imply a population- and/or investigator specificity of algorithms for REE prediction.European Journal of Clinical Nutrition (2007) 61, 582–589. doi:10.1038/sj.ejcn.1602556; published online 29 November 2006 [ABSTRACT FROM AUTHOR]

Ovariectomy (OVX) in animal models is an accepted method to simulate postmenopausal osteoprosis. Vascular endothelial growth factor (VEGF) has been recently shown to play an important role during endochondral bone formation, hypertrophic cartilage remodeling, ossification, and angiogenesis. We hypothesized that reduced VEGF expression in bone contributes to OVX-induced bone loss and tested it in a miniature pig model and in vitro using human osteoblasts. Seventeen primiparous sows (Göttingen miniature pigs) were allocated to two experimental groups when they were 30 months old: a control group ( n = 9) and an OVX group ( n = 8). After 15 months, VEGF levels in lumbar vertebrae were measured by enzyme-linked immunosorbent assay and verified by Western blot analysis. VEGF and its receptor (VEGFR) were localized by immunohistochemistry. Expression of VEGF mRNA was analyzed by real-time reverse-transcription polymerase chain reaction. Differently sulfated glycosaminoglycans were localized in subchondral bone histochemically. Osteoblasts were immunopositive for VEGF. VEGF concentration in the vertebra was 27% lower in OVX miniature pigs. VEGFR-2 could be immunostained on osteoblasts. VEGF mRNA and protein were detectable in the lumbar vertebrae of all animals. In subchondral trabecular bone of OVX animals, significantly more islands of mineralized cartilage containing chondroitin 4- and 6-sulfate or keratan sulfate occurred compared to the control group. The occurrence of remnants of mineralized cartilage in subchondral bone of the OVX group may be caused by a delayed bone turnover due to low VEGF levels. In vitro experiments revealed an increase of VEGF in the supernatant of osteoblasts after incubation with estradiol. In conclusion, estrogen seems to be a key factor for regulation of VEGF expression in bone. Loss of VEGF due to menopause may be a reason for reduction of bone density. [ABSTRACT FROM AUTHOR]

Abstract: Quantitative ultrasound (QUS) measurements at peripheral sites can be used to estimate osteoporotic fracture risk. However, measurements at these sites are less suitable to predict bone mineral density (BMD) or fracture risk at the central skeleton. We investigated whether direct QUS measurements at the femur would allow to estimate dual X-ray absorptiometry (DXA) BMD of the total proximal femur with errors comparable to established DXA accuracy errors. Two independent sets of femora were measured in Kiel (6 f, 4 m, age: 55–90) and Paris (19 f, 20 m age: 45–95) using different benchtop systems in the two laboratories. The femora were scanned in transverse transmission mode using focused US transducers of 500 kHz center frequency. The QUS values were averaged over a region similar to the total hip region of dual X-ray absorptiometry (DXA) measurements. BMD was measured using DXA. SOS and BMD correlated significantly (p <0.0001) in both data sets (R 2 =0.81–0.93). Correlations between BUA and BMD were also significant at p <0.001, but correlation coefficients were lower (R 2 =0.61–0.75). Residual errors for the estimation of BMD were 8%–10% for SOS as predictor, and 14%–16% for BUA as predictor. The residual error of 8 to 10% for the estimation of BMD from SOS is comparable to variabilities among different DXA femur subregions and accuracy errors of femoral DXA measurements caused by the impact of soft tissue. It is substantially smaller than the errors of 13% for the estimation of total femur BMD from spine BMD, 14% for the estimation of total femur BMD from calcaneus SOS or 16% for the estimation of ash weight from DXA. The results of the study show that SOS is able to predict total BMD with adequate accuracy. If femoral BMD could be obtained in vivo with comparable accuracy, femoral QUS would be suited for the assessment of bone status at one of the main osteoporotic fracture sites. [Copyright &y& Elsevier]

Introduction: Assessment of the predictive power of a newly introduced diagnostic technique with regard to fracture risk is frequently limited by the enormous costs and long time periods required for prospective studies. A preliminary estimate of predictive power usually relies on cross-sectional case-control studies in which bone measurements of normal and fractured subjects are compared. The measured discriminatory power is taken as an estimate of predictive power. Because of possible sample selection bias, study participants may have different bone mineral density (BMD) values, and fractured patients may have fractures of different severity levels. The same diagnostic techniques for the measured discriminatory power, expressed as odds ratios, will differ among studies with different patient and control populations. Methods: In this paper, we propose a weighted logistic regression approach to adjust the odds ratio in order to reduce the effect of sampling bias. The weight is derived from age, deformity severity, BMD, and the interactions of these, using the propensity score theory and reference population data. Results: Simulation examples using data from the Osteoporosis and Ultrasound Study (OPUS) demonstrate that such a procedure can effectively reduce the estimation bias of odds ratios introduced by sampling differences, such as for dual x-ray absorptiometry (DXA) scans of the spine and hip as well as various quantitative ultrasound techniques. The derived estimated odds ratios are substantially less biased, and the corresponding 95% confidence intervals contain the true odds ratios from the population data. Conclusions: We conclude that a statistical correction procedure based on propensity scores and weighted logistic regression can effectively reduce the effect of sampling bias on the odds ratios calculated from cross-sectional case-control studies. For a new diagnostic technique, hip BMD and deformity severity information are necessary and likely sufficient to derive the propensity scores required to adjust the measured standardized odds ratios. [ABSTRACT FROM AUTHOR]