3D Analysis of Cortical and Trabecular Bone From Hip DXA:Precision and Trend Assessment Interval in PostmenopausalWomen.

The 3D distribution of the cortical and trabecular bone mass is a critical component in determining the resistance of a bone to fracture that is not assessed in standard dual-energy X-ray absorptiometry (DXA) exams. In this work, we assessed in vivo short-term precision of measurements provided by 3D modeling techniques from DXA scans and trend assessment intervals (TAIs) in postmenopausal women. Subjects included to study precision errors were scanned twice, with repositioning for duplicate hip scans, using either a Lunar iDXA scanner (GE Healthcare, Madison, WI) or a Discovery W scanner (Hologic, Inc., Waltham, MA). Postmenopausal women having baseline and 18-mo follow-up visit were scanned using a Lunar iDXA device to assess TAIs. TAIs indicate what time intervals are required to allow accurate assessment of response to treatment or progression of disease. The 3D-SHAPER software (Galgo Medical, Barcelona, Spain) was used to derive 3D measurements from hip DXA scans. Least significant changes were 10.39 and 8.72 mg/cm3 for integral volumetric bone mineral density (BMD), 9.64 and 9.59 mg/cm3 for trabecular volumetric BMD, and 6.25 and 5.99 mg/cm2 for cortical surface BMD, using the Lunar iDXA and Discovery W scanners, respectively. TAIs in postmenopausal women were 2.9 yr (integral volumetric BMD), 2.6 yr (trabecular volumetric BMD), and 3.5 yr (cortical surface BMD), using the Lunar iDXA scanner. As a comparison, TAIs for areal BMD were 2.8 yr at neck and 2.7 yr at total femur. Least significant changes of measurements provided by 3D modeling techniques from DXA were assessed. TAIs in postmenopausal women were similar to those measured for areal BMD measurements. DXA-derived 3D measurements could potentially provide additional indicators to improve patient monitoring in clinical practices.

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial.

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

Heritability of bone mineral density in a multivariate family-based study.

There is evidence for a genetic contribution to bone mineral density (BMD×). Different loci affecting BMD have been identified by diverse linkage and genome-wide association studies. We studied the heritability of and the correlations among six densitometric phenotypes and four bone mass/fracture phenotypes. For this purpose, we used a family-based study of the genetics of osteoporosis, the Genetic Analysis of Osteoporosis Project. The primary aim of our study was to examine the roles of genetic and environmental factors in determining osteoporosis-related phenotypes. The project consisted of 11 extended families from Spain. All of them were selected through a proband with osteoporosis. BMD was measured using dual-energy X-ray absorptiometry. The proportion of variance of BMD attributable to significant covariates ranged from 25% (for femoral neck BMD) to 48% (for whole-body total BMD). The vast majority of the densitometric phenotypes had highly significant heritability, ranging from 0.252 (whole-body total BMD) to 0.537 (trochanteric BMD) after correcting for covariate effects. All of the densitometric phenotypes showed high and significant genetic correlations (from -0.772 to -1.000) with a low bone mass/osteopenia condition (Affected 3). Our findings provide additional evidence on the heritability of BMD and a strong genetic correlation between BMD and bone mass/fracture phenotypes in a Spanish population. Our results emphasize the importance of detecting genetic risk factors and the benefit of early diagnosis and especially therapeutic and preventive strategies.

Evaluation of bone-related mechanical properties in female patients with long-term remission of Cushing's syndrome using quantitative computed tomography-based finite element analysis.

BACKGROUND: Hypercortisolism in Cushing's syndrome (CS) is associated with bone loss, skeletal fragility, and altered bone quality. No studies evaluated bone geometric and strain-stress values in CS patients after remission thus far. PATIENTS AND METHODS: Thirty-two women with CS in remission (mean age [±SD] 51 ± 11; body mass index [BMI], 27 ± 4 kg/m2; mean time of remission, 120 ± 90 months) and 32 age-, BMI-, and gonadal status-matched female controls. Quantitative computed tomography (QCT) was used to assess volumetric bone mineral density (vBMD) and buckling ratio, cross-sectional area, and average cortical thickness at the level of the proximal femur. Finite element (FE) models were generated from QCT to calculate strain and stress values (maximum principal strain [MPE], maximum strain energy density [SED], maximum Von Mises [VM], and maximum principal stress [MPS]). Areal BMD (aBMD) and trabecular bone score (TBS) were assessed by dual-energy X-ray absorptiometry (2D DXA). RESULTS: Trabecular vBMD at total hip and trochanter were lower in CS as compared with controls (P < .05). Average cortical thickness was lower, and buckling ratio was greater in CS vs controls (P < .01). All strain and stress values were higher in CS patients vs controls (P < .05). 2D DXA-derived measures were similar between patients and controls (P > .05). Prior hypercortisolism predicted both VM (ß .30, P = .014) and MPS (ß .30, P = .015), after adjusting for age, BMI, menopause, delay to diagnosis, and duration of remission. CONCLUSIONS: Women with prior hypercortisolism have reduced trabecular vBMD and impaired bone geometrical and mechanical properties, which may contribute to an elevated fracture risk despite long-term remission.

Fat tissue measurements by dual-energy x-ray absorptiometry: cross-calibration of 3 different fan-beam instruments.

Analysis of total tissue composition and, particularly, body fat measurements has become progressively important in the diagnosis and follow-up of patients with different clinical conditions. Dual-energy X-ray absorptiometry (DXA) fan-beam scanners are widely used to measure body composition, but the development of translational equations to be able to compare data of different scanning systems is necessary. The aim of this study was to assess the extent of agreement for regional measurements of body composition among the following 3 fan-beam DXA scanners: (1) Hologic Discovery (Hologic, Inc., Waltham, MA), (2) Lunar iDXA (GE Healthcare, Madison, WI), and (3) Lunar Prodigy Advance (GE Healthcare, Madison, WI). The study population consisted of 91 adult healthy volunteers (40 males and 51 females; mean age 48.5±14.4yr) who underwent DXA evaluation of the lumbar spine, hip, and whole body in each machine on the same day. Agreement among the 3 scanners was evaluated according to the Bland-Altman method and Lin's concordance correlation coefficient. Results showed a better agreement and concordance for the Lunar iDXA scanner than for any of them with the Hologic scanner. Differences were higher for any tissue or region than for the whole tissue mass. Translational equations were developed to ensure comparability of body composition measurements obtained with each of these 3 scanners.

Defining high risk of osteoporotic fracture: a cross talk between clinical experience and guidelines recommendations.

BACKGROUND: : There is no universally accepted definition for patients at high risk of osteoporotic fracture. OBJECTIVES: : This study aimed to survey Spanish rheumatologists; to obtain opinions about risk factors, and an acceptable definition for patients at high risk of osteoporotic fracture; and to compare daily practice patterns with current osteoporosis guidelines. METHODS: : A total of 174 rheumatologists from throughout Spain completed an online survey about various risk factors for fragility fracture and about the management of patients with osteoporosis in clinical practice. Results were reviewed by a coordinating committee of osteoporosis experts and were compared with published national and international guideline recommendations. RESULTS: : Almost all rheumatologists who completed the survey (99%) consider that a group of patients exists with a high risk of osteoporotic fracture and that this group should be managed appropriately. Previous fracture is considered the most important risk factor, particularly in cases of multiple fracture, severe vertebral fracture, hip fracture, or fracture despite osteoporosis treatment. However, in osteoporosis guidelines, age, bone mineral density, and previous fragility fracture are the most important risk factors for new fracture. Furthermore, Spanish rheumatologists tend to treat patients at high risk of fracture with anabolic therapy (e.g., teriparatide), whereas guidelines make no such recommendation. CONCLUSIONS: : In osteoporosis, a large gap exists between implementation of guideline recommendations and actual clinical practice; this may be due, in part, to heterogeneity among existing guidelines. Thus, inclusion in guidelines of a practical definition of high risk of osteoporotic fracture may provide significant opportunities to improve patient care and prevent future fragility fractures. KEY POINTS: :

Circulating miR-103a-3p and miR-660-5p are associated with bone parameters in patients with controlled acromegaly.

Background Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis. Aims Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters. Patients and methods Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR. Results In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001). Conclusions Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.

3D-DXA: Assessing the Femoral Shape, the Trabecular Macrostructure and the Cortex in 3D from DXA images.

The 3D distribution of the cortical and trabecular bone mass in the proximal femur is a critical component in determining fracture resistance that is not taken into account in clinical routine Dual-energy X-ray Absorptiometry (DXA) examination. In this paper, a statistical shape and appearance model together with a 3D-2D registration approach are used to model the femoral shape and bone density distribution in 3D from an anteroposterior DXA projection. A model-based algorithm is subsequently used to segment the cortex and build a 3D map of the cortical thickness and density. Measurements characterising the geometry and density distribution were computed for various regions of interest in both cortical and trabecular compartments. Models and measurements provided by the "3D-DXA" software algorithm were evaluated using a database of 157 study subjects, by comparing 3D-DXA analyses (using DXA scanners from three manufacturers) with measurements performed by Quantitative Computed Tomography (QCT). The mean point-to-surface distance between 3D-DXA and QCT femoral shapes was 0.93 mm. The mean absolute error between cortical thickness and density estimates measured by 3D-DXA and QCT was 0.33 mm and 72 mg/cm3. Correlation coefficients (R) between the 3D-DXA and QCT measurements were 0.86, 0.93, and 0.95 for the volumetric bone mineral density at the trabecular, cortical, and integral compartments respectively, and 0.91 for the mean cortical thickness. 3D-DXA provides a detailed analysis of the proximal femur, including a separate assessment of the cortical layer and trabecular macrostructure, which could potentially improve osteoporosis management while maintaining DXA as the standard routine modality.

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.

BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.

SNPs in bone-related miRNAs are associated with the osteoporotic phenotype.

Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.

A survey of perceptions with pain management in Spanish inpatients.

The aim of this study was to document the satisfaction with pain management in a Spanish inpatient population and its relationship with pain ratings. Two hundred fifty inpatients of four departments were interviewed: Surgery, Orthopedics, Gynecology, and Internal Medicine. A 32-item questionnaire was used, and the main variables evaluated were pain severity, dissatisfaction with pain management and caregivers, and patient expectations regarding pain relief. Relationships among the variables were analyzed by means of Spearman's correlation between item scores and regression analysis. Median satisfaction scores were consistent with "very satisfied." Mean (SD) worst pain during the past 24 hours was 68.8 (27.5) on a 100 mm visual analogue scale. "Dissatisfaction with Pain Management" correlated positively with "Dissatisfaction with Medical Staff" (0.42), and inversely with "Pain Now" (-0.41) and "Expected Pain Relief" (-0.38). Regression analysis showed that "Dissatisfaction with Pain Management" was dependent on "Pain Now," "Least Pain," and "Dissatisfaction with Medical Staff," with statistically significant beta weight values of 0.277, 0.197, and 0.280, respectively. The study shows that patients were highly satisfied with pain management, even when they were in pain. Moreover, it establishes that patient dissatisfaction with treatment was highly related to the satisfaction with caregivers and pain intensity.

Reduction of trabecular and cortical volumetric bone mineral density at the proximal femur in patients with acromegaly.

OBJECTIVE: Data on dual energy absorptiometry (DXA)-measured bone mineral density (BMD) at the level of the total hip (TH) and femoral neck (FN) in patients with acromegaly (ACRO) are conflicting. Increase in bone size associated with ACRO may limit the reliability of DXA. Our objective is to evaluate trabecular and cortical volumetric BMD (vBMD) across the proximal femur in ACRO patients. DESIGN: Cross sectional study in a clinical research center. PATIENTS: Thirty-five ACRO patients (19 males; mean age, 48±7 years; BMI, 27.5±4.4 kg/m(2); 17 with active disease) and 35 age, gender, and BMI-matched controls. RESULTS: vBMD was assessed by quantitative computed tomography at the level of the TH, FN, trochanter (TR), and intertrochanteric (IT). Trabecular vBMD was lower in both total and active ACRO as compared with controls (P<0.01). Cortical vBMD was lower in ACRO patients (active and controlled) vs controls at both TH and TR sites (P<0.05). These findings were confirmed when only eugonadal patients were analyzed. Both total cross sectional area (CSA) and average cortical thickness (ACT) were greater in ACRO patients vs controls (P<0.05). An inverse association between disease duration and trabecular vBMD at TH (r=-0.42, P=0.023) and IT (r=-0.41, P=0.026) was also found. CONCLUSION: Both cortical and trabecular vBMD are reduced at the proximal femur in ACRO patients, regardless of gender, gonadal status, and disease activity. Disease duration is negatively associated with trabecular vBMD at the TH and IT.

Genetic Contribution of Femoral Neck Bone Geometry to the Risk of Developing Osteoporosis: A Family-Based Study.

Femoral neck geometry parameters are believed to be as good as bone mineral density as independent factors in predicting hip fracture risk. This study was conducted to analyze the roles of genetic and environmental factors in femoral properties measured in a sample of Spanish families with osteoporotic fractures and extended genealogy. The "Genetic Analysis of Osteoporosis (GAO) Project" involved 11 extended families with a total number of 376 individuals. We studied three categorical phenotypes of particular clinical interest and we used a Hip structural analysis based on DXA to analyze 17 strength and geometrical phenotypes of the hip. All the femoral properties had highly significant heritability, ranging from 0.252 to 0.586. The most significant correlations were observed at the genetic level (ρG). Osteoporotic fracture status (Affected 2) and, particularly, low bone mass and osteoporotic condition (Affected 3) had the highest number of significant genetic correlations with diverse femoral properties. In conclusion, our findings suggest that a relatively simple and easy to use method based on DXA studies can provide useful data on properties of the Hip in clinical practice. Furthermore, our results provide a strong motivation for further studies in order to improve the understanding of the pathophysiological mechanism underlying bone architecture and the genetics of osteoporosis.

Exploring correlation between bone metabolism markers and densitometric traits in extended families from Spain.

Osteoporosis is a common multifactorial disorder characterized by low bone mass and reduced bone strength that may cause fragility fractures. In recent years, there have been substantial advancements in the biochemical monitoring of bone metabolism through the measurement of bone turnover markers. Currently, good knowledge of the genetics of such markers has become an indispensable part of osteoporosis research. In this study, we used the Genetic Analysis of Osteoporosis Project to study the genetics of the plasma levels of 12 markers related to bone metabolism and osteoporosis. Plasma phenotypes were determined through biochemical assays and log-transformed values were used together with a set of covariates to model genetic and environmental contributions to phenotypic variation, thus estimating the heritability of each trait. In addition, we studied correlations between the 12 markers and a wide variety of previously described densitometric traits. All of the 12 bone metabolism markers showed significant heritability, ranging from 0.194 for osteocalcin to 0.516 for sclerostin after correcting for covariate effects. Strong genetic correlations were observed between osteocalcin and several bone mineral densitometric traits, a finding with potentially useful diagnostic applications. In addition, suggestive genetic correlations with densitometric traits were observed for leptin and sclerostin. Overall, the few strong and several suggestive genetic correlations point out the existence of a complex underlying genetic architecture for bone metabolism plasma phenotypes and provide a strong motivation for pursuing novel whole-genome gene-mapping strategies.

Effects of an Exercise Programme on Functional Capacity, Body Composition and Risk of Falls in Patients with Cirrhosis: A Randomized Clinical Trial.

UNLABELLED: Patients with cirrhosis often have functional limitations, decreased muscle mass, and a high risk of falls. These variables could improve with exercise. The aim was to study the effects of moderate exercise on functional capacity, body composition and risk of falls in patients with cirrhosis. Twenty-three cirrhotic patients were randomized to an exercise programme (n = 14) or to a relaxation programme (n = 9). Both programmes consisted of a one-hour session 3 days a week for 12 weeks. At the beginning and end of the study, we measured functional capacity using the cardiopulmonary exercise test, evaluated body composition using anthropometry and dual energy X-ray absorptiometry, and estimated risk of falls using the Timed Up&Go test. In the exercise group, cardiopulmonary exercise test showed an increase in total effort time (p<0.001) and ventilatory anaerobic threshold time (p = 0.009). Upper thigh circumference increased and mid-arm and mid-thigh skinfold thickness decreased. Dual energy X-ray absorptiometry showed a decrease in fat body mass (-0.94 kg, 95%CI -0.48 to -1.41, p = 0.003) and an increase in lean body mass (1.05 kg, 95%CI 0.27 to 1.82, p = 0.01), lean appendicular mass (0.38 kg, 95%CI 0.06 to 0.69, p = 0.03) and lean leg mass (0.34 kg, 95%CI 0.10 to 0.57, p = 0.02). The Timed Up&Go test decreased at the end of the study compared to baseline (p = 0.02). No changes were observed in the relaxation group. We conclude that a moderate exercise programme in patients with cirrhosis improves functional capacity, increases muscle mass, and decreases body fat and the Timed Up&Go time. TRIAL REGISTRATION: ClinicalTrials.gov NCT01447537.

Effects of Teriparatide Compared with Risedronate on Recovery After Pertrochanteric Hip Fracture: Results of a Randomized, Active-Controlled, Double-Blind Clinical Trial at 26 Weeks.

BACKGROUND: Osteoporosis drugs might affect fracture-healing. We therefore studied the effects of teriparatide in comparison with risedronate on recovery after pertrochanteric hip fractures. METHODS: The study was a randomized, multicenter, active-controlled, 78-week trial comparing teriparatide (20 µg/day) with risedronate (35 mg/week) initiated within 2 weeks after fixation of a low-trauma pertrochanteric hip fracture (AO/OTA 31-A1 or 31-A2). The main inclusion criteria were a bone mineral density T-score of ≤-2.0 and 25-OH-vitamin D of ≥9.2 ng/mL. During the first 26 weeks, patients received study medication with oral or injectable placebo plus calcium and vitamin D in a double-blinded fashion. Secondary (Timed Up-and-Go [TUG] test, hip pain, Short Form [SF]-36 health status, and safety) and exploratory (radiographic outcomes and ability to walk) 26-week end points are reported. RESULTS: Of the 224 patients who were randomized, 171 (86 teriparatide, 85 risedronate) were included in the analysis. The mean age was 77 ± 8 years, 77% were female, and 26% had a prior history of low-trauma fracture. The teriparatide group completed the TUG test in a shorter time at 6, 12, 18, and 26 weeks (differences of -5.7, -4.4, -3.1, and -3.1 seconds, respectively; p = 0.021 for the overall difference). They also reported less pain on a visual analog scale immediately after the TUG test at 12 and 18 weeks (adjusted absolute differences of 10.6 and 11.9 mm, respectively; p < 0.05). There were no significant between-group differences in the SF-36 score, Charnley hip pain score, ability to walk, or use of walking aids during follow-up. Radiographic healing at 6, 12, and 26 weeks, mechanical failure of the implant (teriparatide, 7; risedronate, 8), loss of reduction (teriparatide, 2; risedronate, 4), and nonunion (0 cases) were not significantly different. Mild hypercalcemia and hyperuricemia were more frequent with teriparatide. CONCLUSIONS: Teriparatide was associated with less pain and a shorter time to complete the TUG test between 6 and 26 weeks compared with risedronate. Other fracture-recovery outcomes were similar. The results should be interpreted with caution as these were secondary end points. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Linkage and association analyses using families identified a locus affecting an osteoporosis-related trait.

Osteoporosis is a common disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increase in bone fragility and in susceptibility to fractures. The genetic basis of osteoporosis is complex and involves multiple genes and environmental factors. Here we introduce a family-based study of the genetics of osteoporosis - the Genetic Analysis of Osteoporosis (GAO) Project - to discover genetic variants affecting osteoporosis-related phenotypes. The GAO Project involved 11 extended families from Barcelona, Spain selected through a proband with osteoporosis (N=367). We performed spine, femur and whole body densitometry for all participants and also analyzed strength and geometrical properties of the hip. Our study focused on 23 densitometric phenotypes that we considered of high clinical relevance and four definitions of low bone mass and fracture status. Pedigree validation was carried out through microsatellite genotyping. The same microsatellites were used to interrogate our data (i) for the replication of previous linkage signals and (ii) for the potential discovery of new linkage signals. The linkage analysis identified one region marked by microsatellite D17S787 showing a strong and significant signal of linkage with femoral shaft cross-sectional moment of inertia (CSMI; LOD=3.18; p=6.5×10(-5)). The chromosomal location marked by microsatellite D17S787 includes several genes, among which two are of particular interest: COL1A1 and SOST, coding for collagen alpha-1 (I) chain and sclerostin, respectively. Follow-up association analysis resulted in only one significant result for rs4792909 from the SOST genomic region (p=0.00248). As a result, we provide strong and significant evidence from both linkage and association analyses that the SOST gene may affect the strength of the femoral shaft. Future investigations should study the relationship between bone mass formation and strength properties of the bones.

Genetic analysis of high bone mass cases from the BARCOS cohort of Spanish postmenopausal women.

The aims of the study were to establish the prevalence of high bone mass (HBM) in a cohort of Spanish postmenopausal women (BARCOS) and to assess the contribution of LRP5 and DKK1 mutations and of common bone mineral density (BMD) variants to a HBM phenotype. Furthermore, we describe the expression of several osteoblast-specific and Wnt-pathway genes in primary osteoblasts from two HBM cases. A 0.6% of individuals (10/1600) displayed Z-scores in the HBM range (sum Z-score >4). While no mutation in the relevant exons of LRP5 was detected, a rare missense change in DKK1 was found (p.Y74F), which cosegregated with the phenotype in a small pedigree. Fifty-five BMD SNPs from Estrada et al. [NatGenet 44:491-501,2012] were genotyped in the HBM cases to obtain risk scores for each individual. In this small group of samples, Z-scores were found inversely related to risk scores, suggestive of a polygenic etiology. There was a single exception, which may be explained by a rare penetrant genetic variant, counterbalancing the additive effect of the risk alleles. The expression analysis in primary osteoblasts from two HBM cases and five controls suggested that IL6R, DLX3, TWIST1 and PPARG are negatively related to Z-score. One HBM case presented with high levels of RUNX2, while the other displayed very low SOX6. In conclusion, we provide evidence of lack of LRP5 mutations and of a putative HBM-causing mutation in DKK1. Additionally, we present SNP genotyping and expression results that suggest additive effects of several genes for HBM.

Psychopathology and psychosocial adjustment in patients with HIV-associated lipodystrophy.

OBJECTIVE: To study whether patients with HIV-1 associated lipodystrophy (LD) on highly active antiretroviral treatment (HAART) have more psychopathology and worse psychosocial adjustment than a similar group without this syndrome. METHODS: In a cross-sectional, observational study we compared 47 HIV-1 infected patients with LD (LD group) with 39 HIV-1 infected patients without LD (non-LD group). All participants were on HAART. The Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI) and the Goldberg Health Questionnaire (GHQ-60) were administered. Levels of familial, work and social adjustment and adjustment to stressful events were evaluated in a semi-structured interview. Clinical information was extracted from the clinical records. RESULTS: In the univariate analysis patients with LD showed higher state anxiety scores (p=0.009) and worse work adjustment (p=0.019) than those without LD. A total of 45.3% of LD patients scored above the cut-off point on the trait anxiety scale, and over 33.3% scored above the cut-off point on the BDI, GHQ and state anxiety scales. However, in multivariate analyses LD was not independently associated with psychopathology or with worse adjustment in the studied areas. CONCLUSIONS: The finding that LD was not a predictor of greater psychopathology or worse psychosocial adjustment in HIV-1 infected patients, despite the high scores found, suggests that factors not taken into account in this study, such as LD severity and self-perception should have been included in the analysis. Further studies including a greater number of variables and a larger sample size will advance our understanding of this complex condition.

[Management of the patient with a high risk of fracture in clinical practice. Results from a survey of 174 Spanish Rheumatologists (OSTEOPAR project)]. / Manejo del paciente con alto riesgo de fractura en la práctica clínica. Resultados de una encuesta a 174 reumatólogos españoles (proyecto OSTEOPAR).

OBJECTIVE: To collect information about diagnosis, classification and treatment of patients at high risk of fracture in the rheumatologist's practice. MATERIAL AND METHODS: A survey was conducted among Spanish rheumatologists. The survey was aimed at gathering data on the physician's healthcare activity, the osteoporosis (OP) and fracture risk factors considered as most relevant, the diagnostic used tests and the treatment indication according to the presence of different risk factors. RESULTS: 99.5% of rheumatologists felt that there is a group of patients with OP at high risk of fracture. Previous fracture was considered the most important risk factor, particularly in case of multiple fractures, severe fractures, hip fracture, or that occurred during treatment. Glucocorticoid treatment, older age and low bone mineral density were considered, in this order, other important risk factors. The number of vertebral fractures was considered the most relevant radiological data, followed by the fracture's chronology and severity. Most of the respondents selected teriparatide as the first treatment option in high-risk patients. CONCLUSIONS: The definition of OP patient with high risk of fracture is not uniform in daily practice, although the majority of rheumatologists considered that having a previous fracture is the most important risk factor, followed by glucocorticoid treatment, older age and low BMD. Anabolic treatment was the approach most commonly used in OP patients with high risk of fracture.