Narrative Review of Effects of Glucagon-Like Peptide-1 Receptor Agonists on Bone Health in People Living with Obesity.

Glucagon-like peptide-1 Receptor agonists (GLP-1Ras) such as liraglutide and semaglutide have been recently approved as medications for chronic weight management in people living with obesity (PwO); GLP-1 may enhance bone metabolism and improve bone quality. However, the effects of GLP-1Ras on skeletal health remain to be determined and that's the purpose of this narrative review. Nevertheless, bone consequences of intentional weight loss interventions in PwO are well known: (i) significant weight loss induced by caloric restriction and bariatric surgery results in accelerated bone turnover and bone loss, and (ii) unlike caloric restriction interventions, PwO experience a substantial deterioration in bone microarchitecture and strength associated with an increased risk of fracture after bariatric surgery especially malabsorptive procedures. Liraglutide seems to have a positive effect on bone material properties despite significant weight loss in several rodent models. However, most of positive effects on bone mineral density and microarchitecture were observed at concentration much higher than approved for obesity care in humans. No data have been reported in preclinical models with semaglutide. The current evidence of the effects of GLP-1Ra on bone health in PwO is limited. Indeed, studies on the use of GLP-1Ra mostly included patients with diabetes who were administered a dose used in this condition, did not have adequate bone parameters as primary endpoints, and had short follow-up periods. Further studies are needed to investigate the bone impact of GLP-1Ra, dual- and triple-receptor agonists for GLP-1, glucose-dependent insulin releasing polypeptide (GIP), and glucagon in PwO.

Proteomics analyses of human plasma reveal triosephosphate isomerase as a potential blood marker of methotrexate resistance in rheumatoid arthritis.

OBJECTIVES: To assess differentially expressed blood proteins between patients with active rheumatoid arthritis (RA) and patients in remission after methotrexate (MTX) treatment, with the aim of identifying a biomarker of methotrexate resistance (MTXR). METHODS: Two populations of RA patients treated with a stable dose of subcutaneous MTX for at least 3 months were constituted according to the DAS28: remission (DAS28 < 2.6; n = 24) and active disease (DAS28 > 3.2; n = 32). The two groups of RA patients were homogeneous regarding their epidemiological characteristics, except for the duration of treatment which was longer in the remission group. After collection of a blood sample, plasma protein digestion was performed, followed by untargeted proteomics analysis. Then, a targeted analysis was performed to confirm the results of the untargeted approach. RESULTS: Untargeted proteomics analysis revealed 8 plasma proteins differentially expressed between the two groups of patients. Among them, triosephosphate isomerase (TPI-1) and glucose-6-phosphate isomerase (GPI), which are main actors of glycolysis, were found down-regulated in the active group. This result was confirmed for TPI-1 in the targeted proteomics analysis. CONCLUSIONS: A first step was achieved in the search for biomarker of MTXR with identification of two actors of glycolysis (TPI-1 and GPI). The next step will be to confirm these results in a larger cohort, including samples from treatment-naive patients, to assess the predictive potential of these protein markers.

An experience- and preference-based EQ-5D-3L value set derived using 18 months of longitudinal data in patients who sustained a fracture: results from the ICUROS.

INTRODUCTION: EQ-5D-3L preference-based value sets are predominately based on hypothetical health states and derived in cross-sectional settings. Therefore, we derived an experience-based value set from a prospective observational study. METHODS: The International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) was a multinational study on fragility fractures, prospectively collecting EQ-5D-3L and Time trade-off (TTO) within two weeks after fracture (including pre-fracture recall), and at 4, 12, and 18 months thereafter. We derived an EQ-5D-3L value set by regressing the TTO values on the ten impairment levels in the EQ-5D-3L. We explored the potential for response shift and whether preferences for domains vary systematically with prior impairment in that domain. Finally, we compared the value set to 25 other EQ-5D-3L preference-based value sets. RESULTS: TTO data were available for 12,954 EQ-5D-3L health states in 4683 patients. All coefficients in the value set had the expected sign, were statistically significant, and increased monotonically with severity of impairment. We found evidence for response shift in mobility, self-care, and usual activities. The value set had good agreement with the only other experience- and preference-based value set, but poor agreement with all hypothetical value sets. CONCLUSIONS: We present an experience- and preference-based value set with high face validity. The study indicates that response shift may be important to account for when deriving value sets. Furthermore, the study suggests that perspective (experienced versus hypothetical) is more important than country setting or demographics for valuation of EQ-5D-3L health states.

Does Adjunction of Autologous Osteoblastic Cells Improve the Results of Core Decompression in Early-stage Femoral Head Osteonecrosis? A Double-blind, Randomized Trial.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a disabling disease that can ultimately progress to collapse of the femoral head, often resulting in THA. Core decompression of the femoral head combined with cell therapies have shown beneficial effects in previous clinical studies in patients with early-stage (Association Research Circulation Osseous [ARCO] Stage I and II) ONFH. However, high-quality evidence confirming the efficacy of this treatment modality is still lacking. QUESTIONS/PURPOSES: (1) Is core decompression combined with autologous osteoblastic cell transplantation superior to core decompression with placebo implantation in relieving disease-associated pain and preventing radiologic ONFH progression in patients with nontraumatic early-stage ONFH? (2) What adverse events occurred in the treatment and control groups? METHODS: This study was a Phase III, multicenter, randomized, double-blind, controlled study conducted from 2011 to 2019 (ClinicalTrails.gov registry number: NCT01529008). Adult patients with ARCO Stage I and II ONFH were randomized (1:1) to receive either core decompression with osteoblastic cell transplantation (5 mL with 20 x 10 6 cells/mL in the study group) or core decompression with placebo (5 mL of solution without cells in the control group) implantation. Thirty percent (68 of 230) of the screened patients were eligible for inclusion in the study; of these, 94% (64 of 68) underwent a bone marrow harvest or sham procedure (extended safety set) and 79% (54 of 68) were treated (study group: 25 patients; control group: 29). Forty-nine patients were included in the efficacy analyses. Similar proportions of patients in each group completed the study at 24 months of follow-up (study group: 44% [11 of 25]; control: 41% [12 of 29]). The study and control groups were comparable in important ways; for example, in the study and control groups, most patients were men (79% [27 of 34] and 87% [26 of 30], respectively) and had ARCO Stage II ONFH (76% [19 of 25] and 83% [24 of 29], respectively); the mean age was 46 and 45 years in the study and control groups, respectively. The follow-up period was 24 months post-treatment. The primary efficacy endpoint was the composite treatment response at 24 months, comprising the clinical response (clinically important improvement in pain from baseline using the WOMAC VA3.1 pain subscale, defined as 10 mm on a 100-mm scale) and radiologic response (the absence of progression to fracture stage [≥ ARCO Stage III], as assessed by conventional radiography and MRI of the hips). Secondary efficacy endpoints included the percentages of patients achieving a composite treatment response, clinical response, and radiologic response at 12 months, and the percentage of patients undergoing THA at 24 months. We maintained a continuous reporting system for adverse events and serious adverse events related to the study treatment, bone marrow aspiration and sham procedure, or other study procedures throughout the study. A planned, unblinded interim analysis of efficacy and adverse events was completed at 12 months. The study was discontinued because our data safety monitoring board recommended terminating the study for futility based on preselected futility stopping rules: conditional power below 0.20 and p = 0.01 to detect an effect size of 10 mm on the 100-mm WOMAC VA3.1 pain subscale (improvement in pain) and the absence of progression to fracture (≥ ARCO Stage III) observed on radiologic assessment, reflecting the unlikelihood that statistically beneficial results would be reached at 24 months after the treatment. RESULTS: There was no difference between the study and control groups in the proportion of patients who achieved a composite treatment response at 24 months (61% [14 of 23] versus 69% [18 of 26]; p = 0.54). There was no difference in the proportion of patients with a treatment response at 12 months between the study and control groups (14 of 21 versus 15 of 23; p = 0.92), clinical response (17 of 21 versus 16 of 23; p = 0.38), and radiologic response (16 of 21 versus 18 of 23; p = 0.87). With the numbers available, at 24 months, there was no difference in the proportion of patients who underwent THA between the study and control groups (24% [six of 25] versus 14% [four of 29]). There were no serious adverse events related to the study treatment, and only one serious adverse event (procedural pain in the study group) was related to bone marrow aspiration. Nonserious adverse events related to the treatment were rare in the study and control groups (4% [one of 25] versus 14% [four of 29]). Nonserious adverse events related to bone marrow or sham aspiration were reported by 15% (five of 34) of patients in the study group and 7% (two of 30) of patients in the control group. CONCLUSION: Our study did not show any advantage of autologous osteoblastic cells to improve the results of core decompression in early-stage (precollapse) ONFH. Adverse events related to treatment were rare and generally mild in both groups, although there might have been a potential risk associated with cell expansion. Based on our findings, we do not recommend the combination of osteoblastic cells and core decompression in patients with early-stage ONFH. Further, well-designed studies should be conducted to explore whether other treatment modalities involving a biological approach could improve the overall results of core decompression. LEVEL OF EVIDENCE: Level II, therapeutic study.

Costs of patient management over 18 months following a hip, clinical vertebral, distal forearm, or proximal humerus fragility fracture in France-results from the ICUROS study.

This observational study prospectively assessed direct and indirect costs related to patient management over 18 months following hip, clinical vertebral, humeral, or distal forearm fracture events in France. It appears that their levels were much higher than the previous estimates, raising the burden of osteoporosis-related fractures on public health expenditures. INTRODUCTION: This prospective observational study assessed the costs related to patient management over the 18-month period following the event of a hip, clinical vertebral, humeral, or distal forearm fracture in France. METHODS: Individuals aged ≥ 50 years old with the diagnosis of a fragility fracture in six French University Hospitals were enrolled in the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS). All resources used over the defined period and related to fracture and the underlying osteoporosis management were collected by questionnaires at baseline, 4 months, 12 months, and 18 months. Information was collected by direct or phone contact completed by patients' records and interviews of partner, family, and general practitioners. Costs were estimated from a societal perspective, including direct and indirect costs. We implemented recursive partitioning analysis (RPA), a statistical learning algorithm to identify predictors of costs. RESULTS: Four hundred thirty-one patients (mean age 72.5 years; 84.6% women) were evaluated. Among them, 17.6% had a prior fracture in the last 5 years. Approximately half of the whole group lived alone in the community, and 56.8% were from a low- or middle-income category. Over the 18-month period of evaluation, total costs (including initial fracture-related and follow-up ones) were 23 926 €, 14 561 €, and 6 905 € for the hip, clinical vertebral, and distal forearm fracture, respectively. Over a year, costs related to a humeral fracture were 10 319 €. The RPA identified mobility impairment prior to fracture as a predictor of increase in costs related to fracture. CONCLUSIONS: Our study for the first time prospectively assessed total costs related to the four main osteoporotic fractures in France. It appears that their levels were much higher than previous estimates, raising the burden of osteoporosis-related fractures on public health expenditures.

Risk factors for shoulder disorders among French workers: prospective cohort study.

OBJECTIVES: Shoulder disorders are common in the working population. This longitudinal study aimed to explore the relationships between personal factors and occupational organisational, psychosocial, and biomechanical factors and the incidence of shoulder disorders. METHODS: A total of 3710 workers in the Pays de la Loire region (Loire Valley area, France) were randomly included by their occupational physician in the Cosali cohort between 2002 and 2005. All workers completed a self-administered questionnaire about personal factors and work exposure, and using a standardised physical examination, occupational physicians diagnosed shoulder disorders. Between 2007 and 2010, 1611 workers were re-examined by their occupational physician. The 1,320 workers free of shoulder disorders at baseline were studied. A conceptual model was developed in which relationships between organisational, psychosocial, biomechanical, and personal factors at baseline and the incidence of shoulder disorders were assumed. Structural equation modelling was used to test the model. RESULTS: Shoulder disorders were directly associated with biomechanical factors and age but not with psychosocial factors. However, skill discretion and psychological demand influenced shoulder disorders indirectly through biomechanical factors. Exposure to a work pace dependent on an automatic rate and to a work pace dependent on customers' demands were associated with biomechanical and psychosocial factors, but not directly to shoulder disorders. CONCLUSIONS: This study identified the complex direct and indirect relationships between occupational factors and shoulder disorders. Our data confirmed our conceptual causation model: organisational and psychosocial factors were associated with biomechanical factors, while biomechanical factors were associated with the incidence of shoulder disorders.

Management of patients at very high risk of osteoporotic fractures through sequential treatments.

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon.

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration.

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.

BACKGROUND: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. METHODS: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. RESULTS: Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. CONCLUSIONS: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).

Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: A Postmarket, Open-Label, Long-Term Historical Control Study with Analysis Detailed per Krellgren-Lawrence Radiologic Osteoarthritis Scale Grade.

BACKGROUND: Intra-articular injections of hyaluronic acid-also called viscosupplementation (VS)-is frequently used for the symptomatic treatment of knee osteoarthritis, a painful and debilitating long-term disease, affecting an important fraction of elderly populations. Severity of knee osteoarthritis is generally described by Kellgren-Lawrence (KL) radiological classification. VS has been widely studied in many clinical trials; however, the results are rarely analyzed in detail according to KL grade. METHOD: A large, clinical, open-label study was performed in 2004-2007 on 1177 patients with knee osteoarthritis, each treated with VS consisting of 3 injections of Arthrum H 2% (LCA Pharmaceutical, Chartres, France). The characteristics of the patients at baseline included demographic profile, body mass index, KL grade, and clinical scores for pain and function using the Western Ontario and McMaster Universities index. Follow-up visits were at 3, 6, and 9 months after VS procedure. This large database was entirely reprocessed in 2019 to provide a separate analysis per KL grade, complemented by the assessment of the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International rates (%) of responders to the treatment. The analysis was carried out for both intention-to-treat and per-protocol completer populations. RESULTS: A primary outcome in the intention-to-treat analysis, variations of the Western Ontario and McMaster Universities index pain subscore from inclusion to the end of the study were 19.8, 19.8, 17.8, and 14.2 for KL grade I to KL grade IV patients, respectively, on a 0 to 100 scale. In the per-protocol analysis, under the same conditions, the variations were 20.6, 19.9, 17.1, and 11.7. All results were significant (P < 0.001) and clinically relevant for each KL grade. Significant improvements were also observed for the Western Ontario and McMaster Universities index function subscore and for the other secondary outcomes. The Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International responders rate reached 72% to 82% for KL grade I through III patients at Month 6 and Month 9. For KL grade IV patients, the maximum rate reached was 47.7% at Month 6. There was evidence that KL grade is a critical parameter, particularly if KL grade IV is present. Other parameters such as gender, body mass index, and age were not identified as prognostic factors of response to VS based on χ2 and odds ratio (95% CI) testing. CONCLUSIONS: Detailed analysis by KL grade supports that VS treatment with Arthrum H 2% applies to a large variety of patients with knee osteoarthritis.

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.

A randomised, double-blind, placebo-controlled study assessing the efficacy of high doses of vitamin D on functional disability in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the short-term efficacy of vitamin D (cholecalciferol) supplementation on functional disability in RA patients. METHODS: 1) Patients: RA (ACR 1987 revised criteria) in non-remission (DAS28 >2.6) whose treatment was not expected to be changed over a 3-month period following inclusion and presenting with vitD deficits (serum 25OHD <30ng/mL). 2) Study design: prospective randomised placebo-controlled trial (NCT02243800). 3) Study arms: either vitD ampoules (cholecalciferol 100,000IU) or placebo. 4) Outcome measures: primary: improvement in patients' functional disability using the Health Assessment questionnaire (HAQ); secondary: improvement in DAS28ESR, DAS28CRP, ESR, CRP, RAID score, fatigue (EVA and FACIT), and SF36. RESULTS: Overall, 59 patients were included, 83.1% females, aged 59.8±10.9 years on average, with RA for 17.0±9.7 years. Thirty patients received placebo and 29 vitD. At 6 months, HAQ scores tended to be increased in the placebo group (+0.08±0.25), while slightly numerically decreased in the vitD group (-0.03±0.23) (p=0.11). After adjusting for age, gender, season, and initial vitD status, the between-group difference achieved statistically significance (p=0.046). After adjusting for age, gender, season, and initial vitD status, there was no significant difference in the secondary criteria between the 2 groups except for ESR and CRP (p=0.002 and 0.04, respectively). CONCLUSIONS: In this randomised, double-blind, placebo-controlled clinical trial in patients with RA and VitD deficiency, high doses of cholecalciferol resulted in a statistically significant improvement in functional disability at month 6, which, however, was clinically not relevant.

Quality of life after hip, vertebral, and distal forearm fragility fractures measured using the EQ-5D-3L, EQ-VAS, and time-trade-off: results from the ICUROS.

INTRODUCTION: The International Costs and Utilities Related to Osteoporotic fractures Study is a multinational observational study set up to describe the costs and quality of life (QoL) consequences of fragility fracture. This paper aims to estimate and compare QoL after hip, vertebral, and distal forearm fracture using time-trade-off (TTO), the EuroQol (EQ) Visual Analogue Scale (EQ-VAS), and the EQ-5D-3L valued using the hypothetical UK value set. METHODS: Data were collected at four time-points for five QoL point estimates: within 2 weeks after fracture (including pre-fracture recall), and at 4, 12, and 18 months after fracture. Health state utility values (HSUVs) were derived for each fracture type and time-point using the three approaches (TTO, EQ-VAS, EQ-5D-3L). HSUV were used to estimate accumulated QoL loss and QoL multipliers. RESULTS: In total, 1410 patients (505 with hip, 316 with vertebral, and 589 with distal forearm fracture) were eligible for analysis. Across all time-points for the three fracture types, TTO provided the highest HSUVs, whereas EQ-5D-3L consistently provided the lowest HSUVs directly after fracture. Except for 13-18 months after distal forearm fracture, EQ-5D-3L generated lower QoL multipliers than the other two methods, whereas no equally clear pattern was observed between EQ-VAS and TTO. On average, the most marked differences between the three approaches were observed immediately after the fracture. CONCLUSIONS: The approach to derive QoL markedly influences the estimated QoL impact of fracture. Therefore the choice of approach may be important for the outcome and interpretation of cost-effectiveness analysis of fracture prevention.

Methotrexate Reduced TNF Bioactivity in Rheumatoid Arthritis Patients Treated with Infliximab.

Objectives. To evaluate methotrexate effect on tumor necrosis factor (TNF) alpha bioactivity during infliximab (IFX) therapy in rheumatoid arthritis (RA) patients and to correlate TNF bioactivity with antibody towards IFX (ATI) development and RA clinical response. Materials and Methods. Thirty-nine active women RA patients despite conventional synthetic disease modifying antirheumatic drugs (csDMARDs) requiring IFX therapy were enrolled, and clinical data and blood samples were recorded at baseline (W0) and at 6 weeks (W6), W22, and W54 of IFX treatment. TNF bioactivity as well as IFX trough and ATI concentrations were assessed on blood samples. Results. TNF bioactivity decreased from W0 to W54 with a large range from W22 at the time of ATI detection. From W22, TNF bioactivity was lower in presence of methotrexate as csDMARD compared to other csDMARDs. IFX trough concentration increased from W0 to W54 with a large range from W22, similarly to TNF bioactivity. Methotrexate therapy prevented ATI presence at W22 and reduced TNF bioactivity compared to other csDMARDs (p = 0.002). Conclusion. This suggests that methotrexate plays a key role in TNF bioactivity and against ATI development.

Clinical trials of new drugs for the treatment of rheumatoid arthritis: focus on early disease.

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases convened a task force of experts in rheumatoid arthritis (RA) and clinical trial methodology to comment on the new draft 'Guideline on clinical investigation of medicinal products for the treatment of RA' released by the European Medicines Agency (EMA). Special emphasis was placed by the group on the development of new drugs for the treatment of early RA. In the absence of a clear definition of early RA, it was suggested that clinical investigations in this condition were conducted in disease-modifying antirheumatic drugs naïve patients with no more than 1 year disease duration. The expert group recommended using an appropriate improvement in disease activity (American College of Rheumatology (ACR) or Simplified/Clinical Disease Activity Index (SDAI/CDAI) response criteria) or low disease activity (by any score) as primary endpoints, with ACR/European League Against Rheumatism remission as a secondary endpoint. Finally, as compelling evidence showed that the Disease Acrivity Score using 28-joint counts (DAS28) might not provide a reliable definition of remission, or sometimes even low disease activity, the group suggested replacing DAS28 as a measurement instrument to evaluate disease activity in RA clinical trials. Proposed alternatives included SDAI, CDAI and Boolean criteria.